Magnetic multicore nanoparticles for hyperthermia--influence of particle immobilization in tumour tissue on magnetic properties.

PubMed

Dutz, Silvio; Kettering, Melanie; Hilger, Ingrid; Müller, Robert; Zeisberger, Matthias

2011-07-01

When using magnetic nanoparticles as a heating source for magnetic particle hyperthermia it is of particular interest to know if the particles are free to move in the interstitial fluid or are fixed to the tumour tissue. The immobilization state determines the relaxation behaviour of the administered particles and thus their specific heating power. To investigate this behaviour, magnetic multicore nanoparticles were injected into experimentally grown tumours in mice and magnetic heating treatment was carried out in an alternating magnetic field (H = 25 kA m(-1), f = 400 kHz). The tested particles were well suited for magnetic heating treatment as they heated a tumour of about 100 mg by about 22 K within the first 60 s. Upon sacrifice, histological tumour examination showed that the particles form spots in the tissue with a mainly homogeneous particle distribution in these spots. The magnetic ex vivo characterization of the removed tumour tissue gave clear evidence for the immobilization of the particles in the tumour tissue because the particles in the tumour showed the same magnetic behaviour as immobilized particles. Therefore, the particles are not able to rotate and a temperature increase due to Brown relaxation can be neglected. To accurately estimate the heating potential of magnetic materials, the respective environments influencing the nanoparticle mobility status have to be taken into account.

Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery

NASA Astrophysics Data System (ADS)

Matsumoto, Yu; Nichols, Joseph W.; Toh, Kazuko; Nomoto, Takahiro; Cabral, Horacio; Miura, Yutaka; Christie, R. James; Yamada, Naoki; Ogura, Tadayoshi; Kano, Mitsunobu R.; Matsumura, Yasuhiro; Nishiyama, Nobuhiro; Yamasoba, Tatsuya; Bae, You Han; Kataoka, Kazunori

2016-06-01

Enhanced permeability in tumours is thought to result from malformed vascular walls with leaky cell-to-cell junctions. This assertion is backed by studies using electron microscopy and polymer casts that show incomplete pericyte coverage of tumour vessels and the presence of intercellular gaps. However, this gives the impression that tumour permeability is static amid a chaotic tumour environment. Using intravital confocal laser scanning microscopy we show that the permeability of tumour blood vessels includes a dynamic phenomenon characterized by vascular bursts followed by brief vigorous outward flow of fluid (named ‘eruptions’) into the tumour interstitial space. We propose that ‘dynamic vents’ form transient openings and closings at these leaky blood vessels. These stochastic eruptions may explain the enhanced extravasation of nanoparticles from the tumour blood vessels, and offer insights into the underlying distribution patterns of an administered drug.

Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo

NASA Astrophysics Data System (ADS)

Kim, K. Jin; Li, Bing; Winer, Jane; Armanini, Mark; Gillett, Nancy; Phillips, Heidi S.; Ferrara, Napoleone

1993-04-01

THE development of new blood vessels (angiogenesis) is required for many physiological processes including embryogenesis, wound healing and corpus luteum formation1,2. Blood vessel neoformation is also important in the pathogenesis of many disorders1-5, particularly rapid growth and metastasis of solid tumours3-5. There are several potential mediators of tumour angiogenesis, including basic and acidic fibroblast growth factors, tumour necrosis factor-α and transforming factors-α and -β 1,2. But it is unclear whether any of these agents actually mediates angiogenesis and tumour growth in vivo. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and an angiogenesis inducer released by a variety of tumour cells and expressed in human tumours in situ. To test whether VEGF may be a tumour angiogenesis factor in vivo, we injected human rhabdomyosar-coma, glioblastoma multiforme or leiomyosarcoma cell lines into nude mice. We report here that treatment with a monoclonal antibody specific for VEGF inhibited the growth of the tumours, but had no effect on the growth rate of the tumour cells In vitro. The density of vessels was decreased in the antibody-treated tumours. These findings demonstrate that inhibition of the action of an angiogenic factor spontaneously produced by tumour cells may suppress tumour growth in vivo.

Folate-targeted amphiphilic cyclodextrin nanoparticles incorporating a fusogenic peptide deliver therapeutic siRNA and inhibit the invasive capacity of 3D prostate cancer tumours.

PubMed

Evans, James C; Malhotra, Meenakshi; Sweeney, Katrina; Darcy, Raphael; Nelson, Colleen C; Hollier, Brett G; O'Driscoll, Caitriona M

2017-10-30

The main barrier to the development of an effective RNA interference (RNAi) therapy is the lack of a suitable delivery vector. Modified cyclodextrins have emerged in recent years for the delivery of siRNA. In the present study, a folate-targeted amphiphilic cyclodextrin was formulated using DSPE-PEG 5000 -folate to target prostate cancer cells. The fusogenic peptide GALA was included in the formulation to aid in the endosomal release of siRNA. Targeted nanoparticles were less than 200nm in size with a neutral surface charge. The complexes were able to bind siRNA and protect it from serum nucleases. Incubation with excess free folate resulted in a significant decrease in the uptake of targeted nanoparticles in LNCaP and PC3 cells, both of which have been reported to have differing pathways of folate uptake. There was a significant reduction in the therapeutic targets, ZEB1 and NRP1 at mRNA and protein level following treatment with targeted complexes. In preliminary functional assays using 3D spheroids, treatment of PC3 tumours with targeted complexes with ZEB1 and NRP1 siRNA resulted in more compact colonies relative to the untargeted controls and inhibited infiltration into the Matrigel™ layer. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of MPS1 Inhibition on Genotoxic Stress Responses in Murine Tumour Cells.

PubMed

Suzuki, Motofumi; Yamamori, Tohru; Yasui, Hironobu; Inanami, Osamu

2016-06-01

The monopolar spindle 1 (MPS1) is a serine/threonine kinase that plays an important role in spindle assembly checkpoint signaling. To determine the possible relationship between MPS1 inhibition and genotoxic stress responses, herein we examined whether MPS1 inhibition influences cellular susceptibility towards two genotoxic treatments, etoposide and ionizing radiation (IR). Two murine tumour cell lines, SCCVII and EMT6, were used. The effect of genotoxic treatments with or without two novel MPS1 inhibitors, NMS-P715 and AZ3146, on cellular survival, cell-cycle distribution, centrosome status and mitotic catastrophe (MC) was evaluated. MPS1 inhibition sensitized murine tumour cells to etoposide but not to IR. In addition, MPS1 inhibition altered cell-cycle progression and exacerbated centrosome abnormalities, resulting in enhanced MC induced by etoposide but not by IR. MPS1 inhibition promotes the etoposide-induced aberrant mitosis and, consequently, the induction of tumour cell death. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy

NASA Astrophysics Data System (ADS)

Chen, Qian; Xu, Ligeng; Liang, Chao; Wang, Chao; Peng, Rui; Liu, Zhuang

2016-10-01

A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours.

Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism.

PubMed

Fais, S

2010-05-01

This review presents a possible new approach against cancer, as represented by inhibition of proton pumps, a mechanism used by tumour cells to avoid intracellular accumulation of toxic substances. Proton pump inhibitors (PPIs) belong to a family of pro-drugs that are currently used in the treatment of peptic diseases needing acidity to be activated. PPIs target the acidic tumour mass, where they are metabolized, thus blocking proton traffic. Proton pump inhibition triggers a rapid cell death as a result of intracellular acidification, caspase activation and early accumulation of reactive oxygen species into tumour cells. As a whole, the devastating effect of PPIs on tumour cells suggest the triggering of a fatal cell toxification. Many human tumours, including melanoma, osteosarcoma, lymphomas and various adenocarcinomas are responsive to PPIs. This appears highly conceivable, in as much as almost all human tumours are acidic and express high levels of proton pumps. Paradoxically, metastatic tumours appear to be more responsive to PPIs being more acidic than the majority of primary tumours. However, two clinical trials test the effectiveness of PPIs in chemosensitizing melanoma and osteosarcoma patients. Indeed, tumour acidity represents a very potent mechanism of chemoresistance. A majority of cytotoxic agents, being weak bases, are quickly protonated outside and do not enter the cells, thus preventing drugs to reach specific cellular targets. Clinical data will provide the proof of concept on the use of PPIs as a new class of antitumour agent with a very low level of systemic toxicity as compared with standard chemotherapeutic agents.

A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways

NASA Astrophysics Data System (ADS)

Spring, Bryan Q.; Bryan Sears, R.; Zheng, Lei Zak; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E.; Schoenfeld, David A.; Pogue, Brian W.; Pereira, Stephen P.; Villa, Elizabeth; Hasan, Tayyaba

2016-04-01

Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)—a multikinase inhibitor—encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities.

Tumour-on-a-chip provides an optical window into nanoparticle tissue transport

NASA Astrophysics Data System (ADS)

Albanese, Alexandre; Lam, Alan K.; Sykes, Edward A.; Rocheleau, Jonathan V.; Chan, Warren C. W.

2013-10-01

Nanomaterials are used for numerous biomedical applications, but the selection of optimal properties for maximum delivery remains challenging. Thus, there is a significant interest in elucidating the nano-bio interactions underlying tissue accumulation. To date, researchers have relied on cell culture or animal models to study nano-bio interactions. However, cell cultures lack the complexity of biological tissues and animal models are prohibitively slow and expensive. Here we report a tumour-on-a-chip system where incorporation of tumour-like spheroids into a microfluidic channel permits real-time analysis of nanoparticle (NP) accumulation at physiological flow conditions. We show that penetration of NPs into the tissue is limited by their diameter and that retention can be improved by receptor targeting. NP transport is predominantly diffusion-limited with convection improving accumulation mostly at the tissue perimeter. A murine tumour model confirms these findings and demonstrates that the tumour-on-a-chip can be useful for screening optimal NP designs prior to in vivo studies.

A truncated form of CD9-partner 1 (CD9P-1), GS-168AT2, potently inhibits in vivo tumour-induced angiogenesis and tumour growth

PubMed Central

Colin, S; Guilmain, W; Creoff, E; Schneider, C; Steverlynck, C; Bongaerts, M; Legrand, E; Vannier, J P; Muraine, M; Vasse, M; Al-Mahmood, S

2011-01-01

Background: Tetraspanins are transmembrane proteins known to contribute to angiogenesis. CD9 partner-1 (CD9P-1/EWI-F), a glycosylated type 1 transmembrane immunoglobulin, is a member of the tetraspanin web, but its role in angiogenesis remains to be elucidated. Methods: We measured the expression of CD9P-1 under angiogenic and angiostatic conditions, and the influence of its knockdown onto capillary structures formation by human endothelial cells (hECs). A truncated form of CDP-1, GS-168AT2, was produced and challenged vs hEC proliferation, migration and capillaries' formation. Its association with CD9P-1, CD9, CD81 and CD151 and the expressions of these later at hEC surface were analysed. Finally, its effects onto in vivo tumour-induced angiogenesis and tumour growth were investigated. Results: Vascular endothelial growth factor (VEGF)-induced capillary tube-like formation was inhibited by tumour necrosis factor α and was associated with a rise in CD9P-1 mRNA expression (P<0.05); accordingly, knockdown of CD9P-1 inhibited VEGF-dependent in vitro angiogenesis. GS-168AT2 dose-dependently inhibited in vitro angiogenesis, hEC migration and proliferation (P<0.05). Co-precipitation experiments suggest that GS-168AT2 corresponds to the sequence by which CD9P-1 physiologically associates with CD81. GS-168AT2 induced the depletion of CD151, CD9 and CD9P-1 from hEC surface, correlating with GS-168AT2 degradation. Finally, in vivo injections of GS-168AT2 inhibited tumour-associated angiogenesis by 53.4±9.5% (P=0.03), and reduced tumour growth of Calu 6 tumour xenografts by 73.9±16.4% (P=0.007) without bodyweight loss. Conclusion: The truncated form of CD9P-1, GS-168AT2, potently inhibits angiogenesis and cell migration by at least the downregulation of CD151 and CD9, which provides the first evidences for the central role of CD9P-1 in tumour-associated angiogenesis and tumour growth. PMID:21863033

MEK inhibition prevents tumour-shed transforming growth factor-β-induced T-regulatory cell augmentation in tumour milieu.

PubMed

Hossain, Dewan M S; Panda, Abir K; Chakrabarty, Sreeparna; Bhattacharjee, Pushpak; Kajal, Kirti; Mohanty, Suchismita; Sarkar, Irene; Sarkar, Diptendra K; Kar, Santosh K; Sa, Gaurisankar

2015-04-01

Tumour progression is associated with immune-suppressive conditions that facilitate the escape of tumour cells from the regimen of immune cells, subsequently paralysing the host defence mechanisms. Induction of CD4(+)  CD25(+)  FoxP3(+) T regulatory (Treg) cells has been implicated in the tumour immune escape mechanism, although the novel anti-cancer treatment strategies targeting Treg cells remain unknown. The focus of this study is to define the interaction between tumour and immune system, i.e. how immune tolerance starts and gradually leads to the induction of adaptive Treg cells in the tumour microenvironment. Our study identified hyperactivated mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -signalling as a potential target for reversing Treg cell augmentation in breast cancer patients. In more mechanistic detail, pharmacological inhibitors of MEK/ERK signalling inhibited transforming growth factor-β (TGF-β) production in tumour cells that essentially blocked TGF-β-SMAD3/SMAD4-mediated induction of CD25/interleukin-2 receptor α on CD4(+) T-cell surface. As a result high-affinity binding of interleukin-2 on those cells was prohibited, causing lack of Janus kinase 1 (JAK1)/JAK3-mediated signal transducer and activator of transcription 3 (STAT3)/STAT5 activation required for FoxP3 expression. Finally, for a more radical approach towards a safe MEK inhibitor, we validate the potential of multi-kinase inhibitor curcumin, especially the nano-curcumin made out of pure curcumin with greater bioavailability; in repealing tumour-shed TGF-β-induced Treg cell augmentation. © 2014 Bose Institute.

MEK inhibition prevents tumour-shed transforming growth factor-β-induced T-regulatory cell augmentation in tumour milieu

PubMed Central

Hossain, Dewan M S; Panda, Abir K; Chakrabarty, Sreeparna; Bhattacharjee, Pushpak; Kajal, Kirti; Mohanty, Suchismita; Sarkar, Irene; Sarkar, Diptendra K; Kar, Santosh K; Sa, Gaurisankar

2015-01-01

Tumour progression is associated with immune-suppressive conditions that facilitate the escape of tumour cells from the regimen of immune cells, subsequently paralysing the host defence mechanisms. Induction of CD4+ CD25+ FoxP3+ T regulatory (Treg) cells has been implicated in the tumour immune escape mechanism, although the novel anti-cancer treatment strategies targeting Treg cells remain unknown. The focus of this study is to define the interaction between tumour and immune system, i.e. how immune tolerance starts and gradually leads to the induction of adaptive Treg cells in the tumour microenvironment. Our study identified hyperactivated mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -signalling as a potential target for reversing Treg cell augmentation in breast cancer patients. In more mechanistic detail, pharmacological inhibitors of MEK/ERK signalling inhibited transforming growth factor-β (TGF-β) production in tumour cells that essentially blocked TGF-β-SMAD3/SMAD4-mediated induction of CD25/interleukin-2 receptor α on CD4+ T-cell surface. As a result high-affinity binding of interleukin-2 on those cells was prohibited, causing lack of Janus kinase 1 (JAK1)/JAK3-mediated signal transducer and activator of transcription 3 (STAT3)/STAT5 activation required for FoxP3 expression. Finally, for a more radical approach towards a safe MEK inhibitor, we validate the potential of multi-kinase inhibitor curcumin, especially the nano-curcumin made out of pure curcumin with greater bioavailability; in repealing tumour-shed TGF-β-induced Treg cell augmentation. PMID:25284464

Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels

PubMed Central

Chauhan, Vikash P.; Martin, John D.; Liu, Hao; Lacorre, Delphine A.; Jain, Saloni R.; Kozin, Sergey V.; Stylianopoulos, Triantafyllos; Mousa, Ahmed S.; Han, Xiaoxing; Adstamongkonkul, Pichet; Popović, Zoran; Huang, Peigen; Bawendi, Moungi G.; Boucher, Yves; Jain, Rakesh K.

2013-01-01

Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors —inexpensive drugs with decades of safe use — could be rapidly repurposed as cancer therapeutics. PMID:24084631

Tumour homing and therapeutic effect of colloidal nanoparticles depend on the number of attached antibodies

PubMed Central

Colombo, Miriam; Fiandra, Luisa; Alessio, Giulia; Mazzucchelli, Serena; Nebuloni, Manuela; De Palma, Clara; Kantner, Karsten; Pelaz, Beatriz; Rotem, Rany; Corsi, Fabio; Parak, Wolfgang J.; Prosperi, Davide

2016-01-01

Active targeting of nanoparticles to tumours can be achieved by conjugation with specific antibodies. Specific active targeting of the HER2 receptor is demonstrated in vitro and in vivo with a subcutaneous MCF-7 breast cancer mouse model with trastuzumab-functionalized gold nanoparticles. The number of attached antibodies per nanoparticle was precisely controlled in a way that each nanoparticle was conjugated with either exactly one or exactly two antibodies. As expected, in vitro we found a moderate increase in targeting efficiency of nanoparticles with two instead of just one antibody attached per nanoparticle. However, the in vivo data demonstrate that best effect is obtained for nanoparticles with only exactly one antibody. There is indication that this is based on a size-related effect. These results highlight the importance of precisely controlling the ligand density on the nanoparticle surface for optimizing active targeting, and that less antibodies can exhibit more effect. PMID:27991503

6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling.

PubMed

Lin, Ruiting; Elf, Shannon; Shan, Changliang; Kang, Hee-Bum; Ji, Quanjiang; Zhou, Lu; Hitosugi, Taro; Zhang, Liang; Zhang, Shuai; Seo, Jae Ho; Xie, Jianxin; Tucker, Meghan; Gu, Ting-Lei; Sudderth, Jessica; Jiang, Lei; Mitsche, Matthew; DeBerardinis, Ralph J; Wu, Shaoxiong; Li, Yuancheng; Mao, Hui; Chen, Peng R; Wang, Dongsheng; Chen, Georgia Zhuo; Hurwitz, Selwyn J; Lonial, Sagar; Arellano, Martha L; Khoury, Hanna J; Khuri, Fadlo R; Lee, Benjamin H; Lei, Qunying; Brat, Daniel J; Ye, Keqiang; Boggon, Titus J; He, Chuan; Kang, Sumin; Fan, Jun; Chen, Jing

2015-11-01

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth

NASA Astrophysics Data System (ADS)

Kim, Sung Eun; Zhang, Li; Ma, Kai; Riegman, Michelle; Chen, Feng; Ingold, Irina; Conrad, Marcus; Turker, Melik Ziya; Gao, Minghui; Jiang, Xuejun; Monette, Sebastien; Pauliah, Mohan; Gonen, Mithat; Zanzonico, Pat; Quinn, Thomas; Wiesner, Ulrich; Bradbury, Michelle S.; Overholtzer, Michael

2016-11-01

The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (<10 nm in diameter) poly(ethylene glycol)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumour xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential.

Lysyl oxidase-like-2 promotes tumour angiogenesis and is a potential therapeutic target in angiogenic tumours.

PubMed

Zaffryar-Eilot, Shelly; Marshall, Derek; Voloshin, Tali; Bar-Zion, Avinoam; Spangler, Rhyannon; Kessler, Ofra; Ghermazien, Haben; Brekhman, Vera; Suss-Toby, Edith; Adam, Dan; Shaked, Yuval; Smith, Victoria; Neufeld, Gera

2013-10-01

Lysyl oxidase-like 2 (LOXL2), a secreted enzyme that catalyzes the cross-linking of collagen, plays an essential role in developmental angiogenesis. We found that administration of the LOXL2-neutralizing antibody AB0023 inhibited bFGF-induced angiogenesis in Matrigel plug assays and suppressed recruitment of angiogenesis promoting bone marrow cells. Small hairpin RNA-mediated inhibition of LOXL2 expression or inhibition of LOXL2 using AB0023 reduced the migration and network-forming ability of endothelial cells, suggesting that the inhibition of angiogenesis results from a direct effect on endothelial cells. To examine the effects of AB0023 on tumour angiogenesis, AB0023 was administered to mice bearing tumours derived from SKOV-3 ovarian carcinoma or Lewis lung carcinoma (LLC) cells. AB0023 treatment significantly reduced the microvascular density in these tumours but did not inhibit tumour growth. However, treatment of mice bearing SKOV-3-derived tumours with AB0023 also promoted increased coverage of tumour vessels with pericytes and reduced tumour hypoxia, providing evidence that anti-LOXL2 therapy results in the normalization of tumour blood vessels. In agreement with these data, treatment of mice bearing LLC-derived tumours with AB0023 improved the perfusion of the tumour-associated vessels as determined by ultrasonography. Improved perfusion and normalization of tumour vessels after treatment with anti-angiogenic agents were previously found to improve the delivery of chemotherapeutic agents into tumours and to result in an enhancement of chemotherapeutic efficiency. Indeed, treatment with AB0023 significantly enhanced the anti-tumourigenic effects of taxol. Our results suggest that inhibition of LOXL2 may prove beneficial for the treatment of angiogenic tumours.

Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.

PubMed

Yao, Zhan; Yaeger, Rona; Rodrik-Outmezguine, Vanessa S; Tao, Anthony; Torres, Neilawattie M; Chang, Matthew T; Drosten, Matthias; Zhao, Huiyong; Cecchi, Fabiola; Hembrough, Todd; Michels, Judith; Baumert, Hervé; Miles, Linde; Campbell, Naomi M; de Stanchina, Elisa; Solit, David B; Barbacid, Mariano; Taylor, Barry S; Rosen, Neal

2017-08-10

Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-γ

PubMed Central

Ribatti, D; Nico, B; Pezzolo, A; Vacca, A; Meazza, R; Cinti, R; Carlini, B; Parodi, F; Pistoia, V; Corrias, M V

2006-01-01

Tumour progression in neuroblastoma (NB) patients correlates with high vascular index. We have previously shown that the ACN NB cell line is tumorigenic and angiogenic in immunodeficient mice, and that interferon-γ (IFN-γ) gene transfer dampens ACN tumorigenicity. As IFN-γ represses lymphocyte-induced tumour angiogenesis in various murine models and inhibits proliferation and migration of human endothelial cells, we have investigated the antiangiogenic activity of tumour-derived IFN-γ and the underlying mechanism(s). In addition, we characterised the tumour vasculature of the ACN xenografts, using the chick embryo chorioallantoic membrane assay. We show that the ACN/IFN-γ xenografts had a lower microvessel density and less in vivo angiogenic potential than the vector-transfected ACN/neo. The vascular channels of both xenografts were formed by a mixed endothelial cell population of murine and human origin, as assessed by the FICTION (fluorescence immunophenotyping and interphase cytogenetics) technique. With respect to ACN/neo, the ACN/IFN-γ xenografts showed more terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling-positive human and murine endothelial cells, suggesting that inhibition of angiogenesis by IFN-γ was dependent on the induction of apoptosis, likely mediated by nitric oxide. Once the dual origin of tumour vasculature is confirmed in NB patients, the xenograft model described here will prove useful in testing the efficacy of different antiangiogenic compounds. PMID:16721359

Captopril inhibits tumour growth in a xenograft model of human renal cell carcinoma.

PubMed Central

Hii, S. I.; Nicol, D. L.; Gotley, D. C.; Thompson, L. C.; Green, M. K.; Jonsson, J. R.

1998-01-01

The effect of captopril on tumour growth was examined in a xenograft model of human renal cell carcinoma (RCC). Inoculation of the human RCC cell line SN12K-1 (10(6) cells) under the left kidney capsule of severe combined immunodeficient (SCID) mice resulted in the growth of large tumours, with an increase in weight of the inoculated kidney of 3.69+/-1.63-fold (mean+/-s.d.) when compared with the contralateral normal kidney. In mice treated with captopril (19 mg kg(-1) day(-1) or 94 mg kg(-1) day(-1) administered in the drinking water), there was a significant dose-related reduction in tumour development; the tumour bearing kidneys weighed 1.9+/-0.42 and 1.55+/-0.42 times the normal kidneys, respectively (P< 0.05 compared with untreated animals). In vitro, captopril at clinically achievable doses (0.1-10 microM) had no significant effect on the incorporation of [3H]thymidine into SN12K-1 cells. Thus, this highly significant attenuation by captopril of in vivo tumour growth does not appear to be due to a direct effect on the proliferation of the tumour cells. Further studies are required to determine the mechanism of inhibition of tumour growth by captopril, in particular to evaluate the role of angiotensin II in this process. Images Figure 1 PMID:9528828

In vivo covalent cross-linking of photon-converted rare-earth nanostructures for tumour localization and theranostics

NASA Astrophysics Data System (ADS)

Ai, Xiangzhao; Ho, Chris Jun Hui; Aw, Junxin; Attia, Amalina Binte Ebrahim; Mu, Jing; Wang, Yu; Wang, Xiaoyong; Wang, Yong; Liu, Xiaogang; Chen, Huabing; Gao, Mingyuan; Chen, Xiaoyuan; Yeow, Edwin K. L.; Liu, Gang; Olivo, Malini; Xing, Bengang

2016-01-01

The development of precision nanomedicines to direct nanostructure-based reagents into tumour-targeted areas remains a critical challenge in clinics. Chemical reaction-mediated localization in response to tumour environmental perturbations offers promising opportunities for rational design of effective nano-theranostics. Here, we present a unique microenvironment-sensitive strategy for localization of peptide-premodified upconversion nanocrystals (UCNs) within tumour areas. Upon tumour-specific cathepsin protease reactions, the cleavage of peptides induces covalent cross-linking between the exposed cysteine and 2-cyanobenzothiazole on neighbouring particles, thus triggering the accumulation of UCNs into tumour site. Such enzyme-triggered cross-linking of UCNs leads to enhanced upconversion emission upon 808 nm laser irradiation, and in turn amplifies the singlet oxygen generation from the photosensitizers attached on UCNs. Importantly, this design enables remarkable tumour inhibition through either intratumoral UCNs injection or intravenous injection of nanoparticles modified with the targeting ligand. Our strategy may provide a multimodality solution for effective molecular sensing and site-specific tumour treatment.

Loss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR

PubMed Central

Henze, Anne-Theres; Garvalov, Boyan K.; Seidel, Sascha; Cuesta, Angel M.; Ritter, Mathias; Filatova, Alina; Foss, Franziska; Dopeso, Higinio; Essmann, Clara L.; Maxwell, Patrick H.; Reifenberger, Guido; Carmeliet, Peter; Acker-Palmer, Amparo; Acker, Till

2014-01-01

Solid tumours are exposed to microenvironmental factors such as hypoxia that normally inhibit cell growth. However, tumour cells are capable of counteracting these signals through mechanisms that are largely unknown. Here we show that the prolyl hydroxylase PHD3 restrains tumour growth in response to microenvironmental cues through the control of EGFR. PHD3 silencing in human gliomas or genetic deletion in a murine high-grade astrocytoma model markedly promotes tumour growth and the ability of tumours to continue growing under unfavourable conditions. The growth-suppressive function of PHD3 is independent of the established PHD3 targets HIF and NF-κB and its hydroxylase activity. Instead, loss of PHD3 results in hyperphosphorylation of epidermal growth factor receptor (EGFR). Importantly, epigenetic/genetic silencing of PHD3 preferentially occurs in gliomas without EGFR amplification. Our findings reveal that PHD3 inactivation provides an alternative route of EGFR activation through which tumour cells sustain proliferative signalling even under conditions of limited oxygen availability. PMID:25420773

Augmenting drug–carrier compatibility improves tumour nanotherapy efficacy

PubMed Central

Zhao, Yiming; Fay, François; Hak, Sjoerd; Manuel Perez-Aguilar, Jose; Sanchez-Gaytan, Brenda L.; Goode, Brandon; Duivenvoorden, Raphaël; de Lange Davies, Catharina; Bjørkøy, Astrid; Weinstein, Harel; Fayad, Zahi A.; Pérez-Medina, Carlos; Mulder, Willem J. M.

2016-01-01

A major goal of cancer nanotherapy is to use nanoparticles as carriers for targeted delivery of anti-tumour agents. The drug–carrier association after intravenous administration is essential for efficient drug delivery to the tumour. However, a large number of currently available nanocarriers are self-assembled nanoparticles whose drug-loading stability is critically affected by the in vivo environment. Here we used in vivo FRET imaging to systematically investigate how drug–carrier compatibility affects drug release in a tumour mouse model. We found the drug's hydrophobicity and miscibility with the nanoparticles are two independent key parameters that determine its accumulation in the tumour. Next, we applied these findings to improve chemotherapeutic delivery by augmenting the parent drug's compatibility; as a result, we achieved better antitumour efficacy. Our results help elucidate nanomedicines' in vivo fate and provide guidelines for efficient drug delivery. PMID:27071376

Selenium nanoparticles inhibit Staphylococcus aureus growth

PubMed Central

Tran, Phong A; Webster, Thomas J

2011-01-01

Staphylococcus aureus is a key bacterium commonly found in numerous infections. S. aureus infections are difficult to treat due to their biofilm formation and documented antibiotic resistance. While selenium has been used for a wide range of applications including anticancer applications, the effects of selenium nanoparticles on microorganisms remain largely unknown to date. The objective of this in vitro study was thus to examine the growth of S. aureus in the presence of selenium nanoparticles. Results of this study provided the first evidence of strongly inhibited growth of S. aureus in the presence of selenium nanoparticles after 3, 4, and 5 hours at 7.8, 15.5, and 31 μg/mL. The percentage of live bacteria also decreased in the presence of selenium nanoparticles. Therefore, this study suggests that selenium nanoparticles may be used to effectively prevent and treat S. aureus infections and thus should be further studied for such applications. PMID:21845045

Isthmin is a novel secreted angiogenesis inhibitor that inhibits tumour growth in mice

PubMed Central

Xiang, Wei; Ke, Zhiyuan; Zhang, Yong; Ho-Yuet Cheng, Grace; Irwan, Ishak Darryl; Sulochana, K N; Potturi, Padma; Wang, Zhengyuan; Yang, He; Wang, Jingyu; Zhuo, Lang; Kini, R Manjunatha; Ge, Ruowen

2011-01-01

Abstract Anti-angiogenesis represents a promising therapeutic strategy for the treatment of various malignancies. Isthmin (ISM) is a gene highly expressed in the isthmus of the midbrain–hindbrain organizer in Xenopus with no known functions. It encodes a secreted 60 kD protein containing a thrombospondin type 1 repeat domain in the central region and an adhesion-associated domain in MUC4 and other proteins (AMOP) domain at the C-terminal. In this work, we demonstrate that ISM is a novel angiogenesis inhibitor. Recombinant mouse ISM inhibited endothelial cell (EC) capillary network formation on Matrigel through its C-terminal AMOP domain. It also suppressed vascular endothelial growth factor (VEGF)-basic fibroblast growth factor (bFGF) induced in vivo angiogenesis in mouse. It mitigated VEGF-stimulated EC proliferation without affecting EC migration. Furthermore, ISM induced EC apoptosis in the presence of VEGF through a caspase-dependent pathway. ISM binds to αvβ5 integrin on EC surface and supports EC adhesion. Overexpression of ISM significantly suppressed mouse B16 melanoma tumour growth through inhibition of tumour angiogenesis without affecting tumour cell proliferation. Knockdown of isthmin in zebrafish embryos using morpholino antisense oligonucleotides led to disorganized intersegmen-tal vessels in the trunk. Our results demonstrate that ISM is a novel endogenous angiogenesis inhibitor with functions likely in physiological as well as pathological angiogenesis. PMID:19874420

Augmenting drug–carrier compatibility improves tumour nanotherapy efficacy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Yiming; Fay, Francois; Hak, Sjoerd

A major goal of cancer nanotherapy is to use nanoparticles as carriers for targeted delivery of anti-tumour agents. The drug–carrier association after intravenous administration is essential for efficient drug delivery to the tumour. However, a large number of currently available nanocarriers are self-assembled nanoparticles whose drug-loading stability is critically affected by the in vivo environment. Here we used in vivo FRET imaging to systematically investigate how drug–carrier compatibility affects drug release in a tumour mouse model. We found the drug’s hydrophobicity and miscibility with the nanoparticles are two independent key parameters that determine its accumulation in the tumour. Next, wemore » applied these findings to improve chemotherapeutic delivery by augmenting the parent drug’s compatibility; as a result, we achieved better antitumour efficacy. Lastly, our results help elucidate nanomedicines’ in vivo fate and provide guidelines for efficient drug delivery.« less

Augmenting drug–carrier compatibility improves tumour nanotherapy efficacy

DOE PAGES

Zhao, Yiming; Fay, Francois; Hak, Sjoerd; ...

2016-04-13

A major goal of cancer nanotherapy is to use nanoparticles as carriers for targeted delivery of anti-tumour agents. The drug–carrier association after intravenous administration is essential for efficient drug delivery to the tumour. However, a large number of currently available nanocarriers are self-assembled nanoparticles whose drug-loading stability is critically affected by the in vivo environment. Here we used in vivo FRET imaging to systematically investigate how drug–carrier compatibility affects drug release in a tumour mouse model. We found the drug’s hydrophobicity and miscibility with the nanoparticles are two independent key parameters that determine its accumulation in the tumour. Next, wemore » applied these findings to improve chemotherapeutic delivery by augmenting the parent drug’s compatibility; as a result, we achieved better antitumour efficacy. Lastly, our results help elucidate nanomedicines’ in vivo fate and provide guidelines for efficient drug delivery.« less

Self-assembling chimeric polypeptide-doxorubicin conjugate nanoparticles that abolish tumours after a single injection

NASA Astrophysics Data System (ADS)

Andrew Mackay, J.; Chen, Mingnan; McDaniel, Jonathan R.; Liu, Wenge; Simnick, Andrew J.; Chilkoti, Ashutosh

2009-12-01

New strategies to self-assemble biocompatible materials into nanoscale, drug-loaded packages with improved therapeutic efficacy are needed for nanomedicine. To address this need, we developed artificial recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into sub-100-nm-sized, near-monodisperse nanoparticles on conjugation of diverse hydrophobic molecules, including chemotherapeutics. These CPs consist of a biodegradable polypeptide that is attached to a short Cys-rich segment. Covalent modification of the Cys residues with a structurally diverse set of hydrophobic small molecules, including chemotherapeutics, leads to spontaneous formation of nanoparticles over a range of CP compositions and molecular weights. When used to deliver chemotherapeutics to a murine cancer model, CP nanoparticles have a fourfold higher maximum tolerated dose than free drug, and induce nearly complete tumour regression after a single dose. This simple strategy can promote co-assembly of drugs, imaging agents and targeting moieties into multifunctional nanomedicines.

Green synthesis of fluorescent carbon dots from spices for in vitro imaging and tumour cell growth inhibition

PubMed Central

Gallo, Juan; Cerqueira, María de Fátima; Menéndez-Miranda, Mario; Costa-Fernández, José Manuel; Diéguez, Lorena; Espiña, Begoña

2018-01-01

Carbon dots have demonstrated great potential as luminescent nanoparticles in bioapplications. Although such nanoparticles appear to exhibit low toxicity compared to other metal luminescent nanomaterials, today we know that the toxicity of carbon dots (C-dots) strongly depends on the protocol of fabrication. In this work, aqueous fluorescent C-dots have been synthesized from cinnamon, red chilli, turmeric and black pepper, by a one-pot green hydrothermal method. The synthesized C-dots were firstly characterized by means of UV–vis, fluorescence, Fourier transform infrared and Raman spectroscopy, dynamic light scattering and transmission electron microscopy. The optical performance showed an outstanding ability for imaging purposes, with quantum yields up to 43.6%. Thus, the cytotoxicity of the above mentioned spice-derived C-dots was evaluated in vitro in human glioblastoma cells (LN-229 cancer cell line) and in human kidney cells (HK-2 non-cancerous cell line). Bioimaging and viability studies were performed with different C-dot concentrations from 0.1 to 2 mg·mL−1, exhibiting a higher uptake of C-dots in the cancer cultures compared to the non-cancerous cells. Results showed that the spice-derived C-dots inhibited cell viability dose-dependently after a 24 h incubation period, displaying a higher toxicity in LN-229, than in HK-2 cells. As a control, C-dots synthesized from citric acid did not show any significant toxicity in either cancerous or non-cancerous cells, implying that the tumour cell growth inhibition properties observed in the spice-derived C-dots can be attributed to the starting material employed for their fabrication. These results evidence that functional groups in the surface of the C-dots might be responsible for the selective cytotoxicity, as suggested by the presence of piperine in the surface of black pepper C-dots analysed by ESI-QTOF-MS. PMID:29527430

Tyrosine- and tryptophan-coated gold nanoparticles inhibit amyloid aggregation of insulin.

PubMed

Dubey, Kriti; Anand, Bibin G; Badhwar, Rahul; Bagler, Ganesh; Navya, P N; Daima, Hemant Kumar; Kar, Karunakar

2015-12-01

Here, we have strategically synthesized stable gold (AuNPs(Tyr), AuNPs(Trp)) and silver (AgNPs(Tyr)) nanoparticles which are surface functionalized with either tyrosine or tryptophan residues and have examined their potential to inhibit amyloid aggregation of insulin. Inhibition of both spontaneous and seed-induced aggregation of insulin was observed in the presence of AuNPs(Tyr), AgNPs(Tyr), and AuNPs(Trp) nanoparticles. These nanoparticles also triggered the disassembly of insulin amyloid fibrils. Surface functionalization of amino acids appears to be important for the inhibition effect since isolated tryptophan and tyrosine molecules did not prevent insulin aggregation. Bioinformatics analysis predicts involvement of tyrosine in H-bonding interactions mediated by its C=O, -NH2, and aromatic moiety. These results offer significant opportunities for developing nanoparticle-based therapeutics against diseases related to protein aggregation.

Isthmin is a novel secreted angiogenesis inhibitor that inhibits tumour growth in mice.

PubMed

Xiang, Wei; Ke, Zhiyuan; Zhang, Yong; Cheng, Grace Ho-Yuet; Irwan, Ishak Darryl; Sulochana, K N; Potturi, Padma; Wang, Zhengyuan; Yang, He; Wang, Jingyu; Zhuo, Lang; Kini, R Manjunatha; Ge, Ruowen

2011-02-01

Anti-angiogenesis represents a promising therapeutic strategy for the treatment of various malignancies. Isthmin (ISM) is a gene highly expressed in the isthmus of the midbrain-hindbrain organizer in Xenopus with no known functions. It encodes a secreted 60 kD protein containing a thrombospondin type 1 repeat domain in the central region and an adhesion-associated domain in MUC4 and other proteins (AMOP) domain at the C-terminal. In this work, we demonstrate that ISM is a novel angiogenesis inhibitor. Recombinant mouse ISM inhibited endothelial cell (EC) capillary network formation on Matrigel through its C-terminal AMOP domain. It also suppressed vascular endothelial growth factor (VEGF)-basic fibroblast growth factor (bFGF) induced in vivo angiogenesis in mouse. It mitigated VEGF-stimulated EC proliferation without affecting EC migration. Furthermore, ISM induced EC apoptosis in the presence of VEGF through a caspase-dependent pathway. ISM binds to αvβ(5) integrin on EC surface and supports EC adhesion. Overexpression of ISM significantly suppressed mouse B16 melanoma tumour growth through inhibition of tumour angiogenesis without affecting tumour cell proliferation. Knockdown of isthmin in zebrafish embryos using morpholino antisense oligonucleotides led to disorganized intersegmental vessels in the trunk. Our results demonstrate that ISM is a novel endogenous angiogenesis inhibitor with functions likely in physiological as well as pathological angiogenesis. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation.

PubMed

Kiss, Izabella; Unger, Christine; Huu, Chi Nguyen; Atanasov, Atanas Georgiev; Kramer, Nina; Chatruphonprasert, Waranya; Brenner, Stefan; McKinnon, Ruxandra; Peschel, Andrea; Vasas, Andrea; Lajter, Ildiko; Kain, Renate; Saiko, Philipp; Szekeres, Thomas; Kenner, Lukas; Hassler, Melanie R; Diaz, Rene; Frisch, Richard; Dirsch, Verena M; Jäger, Walter; de Martin, Rainer; Bochkov, Valery N; Passreiter, Claus M; Peter-Vörösmarty, Barbara; Mader, Robert M; Grusch, Michael; Dolznig, Helmut; Kopp, Brigitte; Zupko, Istvan; Hohmann, Judit; Krupitza, Georg

2015-01-28

An apolar extract of the traditional medicinal plant Neurolaena lobata inhibited the expression of the NPM/ALK chimera, which is causal for the majority of anaplastic large cell lymphomas (ALCLs). Therefore, an active principle of the extract, the furanoheliangolide sesquiterpene lactone lobatin B, was isolated and tested regarding the inhibition of ALCL expansion and tumour cell intravasation through the lymphendothelium. ALCL cell lines, HL-60 cells and PBMCs were treated with plant compounds and the ALK inhibitor TAE-684 to measure mitochondrial activity, proliferation and cell cycle progression and to correlate the results with protein- and mRNA-expression of selected gene products. Several endpoints indicative for cell death were analysed after lobatin B treatment. Tumour cell intravasation through lymphendothelial monolayers was measured and potential causal mechanisms were investigated analysing NF-κB- and cytochrome P450 activity, and 12(S)-HETE production. Lobatin B inhibited the expression of NPM/ALK, JunB and PDGF-Rβ, and attenuated proliferation of ALCL cells by arresting them in late M phase. Mitochondrial activity remained largely unaffected upon lobatin B treatment. Nevertheless, caspase 3 became activated in ALCL cells. Also HL-60 cell proliferation was attenuated whereas PBMCs of healthy donors were not affected by lobatin B. Additionally, tumour cell intravasation, which partly depends on NF-κB, was significantly suppressed by lobatin B most likely due to its NF-κB-inhibitory property. Lobatin B, which was isolated from a plant used in ethnomedicine, targets malignant cells by at least two properties: I) inhibition of NPM/ALK, thereby providing high specificity in combating this most prevalent fusion protein occurring in ALCL; II) inhibition of NF-κB, thereby not affecting normal cells with low constitutive NF-κB activity. This property also inhibits tumour cell intravasation into the lymphatic system and may provide an option to manage this

Cellular Binding of Anionic Nanoparticles is Inhibited by Serum Proteins Independent of Nanoparticle Composition.

PubMed

Fleischer, Candace C; Kumar, Umesh; Payne, Christine K

2013-09-01

Nanoparticles used in biological applications encounter a complex mixture of extracellular proteins. Adsorption of these proteins on the nanoparticle surface results in the formation of a "protein corona," which can dominate the interaction of the nanoparticle with the cellular environment. The goal of this research was to determine how nanoparticle composition and surface modification affect the cellular binding of protein-nanoparticle complexes. We examined the cellular binding of a collection of commonly used anionic nanoparticles: quantum dots, colloidal gold nanoparticles, and low-density lipoprotein particles, in the presence and absence of extracellular proteins. These experiments have the advantage of comparing different nanoparticles under identical conditions. Using a combination of fluorescence and dark field microscopy, flow cytometry, and spectroscopy, we find that cellular binding of these anionic nanoparticles is inhibited by serum proteins independent of nanoparticle composition or surface modification. We expect these results will aid in the design of nanoparticles for in vivo applications.

Identification of infusion strategy for achieving repeatable nanoparticle distribution and quantification of thermal dosage using micro-CT Hounsfield unit in magnetic nanoparticle hyperthermia.

PubMed

LeBrun, Alexander; Joglekar, Tejashree; Bieberich, Charles; Ma, Ronghui; Zhu, Liang

2016-01-01

The objective of this study was to identify an injection strategy leading to repeatable nanoparticle deposition patterns in tumours and to quantify volumetric heat generation rate distribution based on micro-CT Hounsfield unit (HU) in magnetic nanoparticle hyperthermia. In vivo animal experiments were performed on graft prostatic cancer (PC3) tumours in immunodeficient mice to investigate whether lowering ferrofluid infusion rate improves control of the distribution of magnetic nanoparticles in tumour tissue. Nanoparticle distribution volume obtained from micro-CT scan was used to evaluate spreading of the nanoparticles from the injection site in tumours. Heating experiments were performed to quantify relationships among micro-CT HU values, local nanoparticle concentrations in the tumours, and the ferrofluid-induced volumetric heat generation rate (q(MNH)) when nanoparticles were subject to an alternating magnetic field. An infusion rate of 3 µL/min was identified to result in the most repeatable nanoparticle distribution in PC3 tumours. Linear relationships have been obtained to first convert micro-CT greyscale values to HU values, then to local nanoparticle concentrations, and finally to nanoparticle-induced q(MNH) values. The total energy deposition rate in tumours was calculated and the observed similarity in total energy deposition rates in all three infusion rate groups suggests improvement in minimising nanoparticle leakage from the tumours. The results of this study demonstrate that micro-CT generated q(MNH) distribution and tumour physical models improve predicting capability of heat transfer simulation for designing reliable treatment protocols using magnetic nanoparticle hyperthermia.

Gold Nanoparticles and Microwave Irradiation Inhibit Beta-Amyloid Amyloidogenesis

NASA Astrophysics Data System (ADS)

Araya, Eyleen; Olmedo, Ivonne; Bastus, Neus G.; Guerrero, Simón; Puntes, Víctor F.; Giralt, Ernest; Kogan, Marcelo J.

2008-11-01

Peptide-Gold nanoparticles selectively attached to β-amyloid protein (Aβ) amyloidogenic aggregates were irradiated with microwave. This treatment produces dramatic effects on the Aβ aggregates, inhibiting both the amyloidogenesis and the restoration of the amyloidogenic potential. This novel approach offers a new strategy to inhibit, locally and remotely, the amyloidogenic process, which could have application in Alzheimer’s disease therapy. We have studied the irradiation effect on the amyloidogenic process in the presence of conjugates peptide-nanoparticle by transmission electronic microscopy observations and by Thioflavine T assays to quantify the amount of fibrils in suspension. The amyloidogenic aggregates rather than the amyloid fibrils seem to be better targets for the treatment of the disease. Our results could contribute to the development of a new therapeutic strategy to inhibit the amyloidogenic process in Alzheimer’s disease.

Inhibition effects of protein-conjugated amorphous zinc sulfide nanoparticles on tumor cells growth

NASA Astrophysics Data System (ADS)

Cao, Ying; Wang, Hua-Jie; Cao, Cui; Sun, Yuan-Yuan; Yang, Lin; Wang, Bao-Qing; Zhou, Jian-Guo

2011-07-01

In this article, a facile and environmentally friendly method was applied to fabricate BSA-conjugated amorphous zinc sulfide (ZnS) nanoparticles using bovine serum albumin (BSA) as the matrix. Transmission electron microscopy analysis indicated that the stable and well-dispersed nanoparticles with the diameter of 15.9 ± 2.1 nm were successfully prepared. The energy dispersive X-ray, X-ray powder diffraction, Fourier transform infrared spectrograph, high resolution transmission electron microscope, and selected area electron diffraction measurements showed that the obtained nanoparticles had the amorphous structure and the coordination occurred between zinc sulfide surfaces and BSA in the nanoparticles. In addition, the inhibition effects of BSA-conjugated amorphous zinc sulfide nanoparticles on tumor cells growth were described in detail by cell viability analysis, optical and electron microscopy methods. The results showed that BSA-conjugated amorphous zinc sulfide nanoparticles could inhibit the metabolism and proliferation of human hepatocellular carcinoma cells, and the inhibition was dose dependent. The half maximal inhibitory concentration (IC50) was 0.36 mg/mL. Overall, this study suggested that BSA-conjugated amorphous zinc sulfide nanoparticles had the application potential as cytostatic agents and BSA in the nanoparticles could provide the modifiable site for the nanoparticles to improve their bioactivity or to endow them with the target function.

The synthetic peptide P111-136 derived from the C-terminal domain of heparin affin regulatory peptide inhibits tumour growth of prostate cancer PC-3 cells

PubMed Central

2011-01-01

Background Heparin affin regulatory peptide (HARP), also called pleiotrophin, is a heparin-binding, secreted factor that is overexpressed in several tumours and associated to tumour growth, angiogenesis and metastasis. The C-terminus part of HARP composed of amino acids 111 to 136 is particularly involved in its biological activities and we previously established that a synthetic peptide composed of the same amino acids (P111-136) was capable of inhibiting the biological activities of HARP. Here we evaluate the ability of P111-136 to inhibit in vitro and in vivo the growth of a human tumour cell line PC-3 which possess an HARP autocrine loop. Methods A total lysate of PC-3 cells was incubated with biotinylated P111-136 and pulled down for the presence of the HARP receptors in Western blot. In vitro, the P111-136 effect on HARP autocrine loop in PC-3 cells was determined by colony formation in soft agar. In vivo, PC-3 cells were inoculated in the flank of athymic nude mice. Animals were treated with P111-136 (5 mg/kg/day) for 25 days. Tumour volume was evaluated during the treatment. After the animal sacrifice, the tumour apoptosis and associated angiogenesis were evaluated by immunohistochemistry. In vivo anti-angiogenic effect was confirmed using a mouse Matrigel™ plug assay. Results Using pull down experiments, we identified the HARP receptors RPTPβ/ζ, ALK and nucleolin as P111-136 binding proteins. In vitro, P111-136 inhibits dose-dependently PC-3 cell colony formation. Treatment with P111-136 inhibits significantly the PC-3 tumour growth in the xenograft model as well as tumour angiogenesis. The angiostatic effect of P111-136 on HARP was also confirmed using an in vivo Matrigel™ plug assay in mice Conclusions Our results demonstrate that P111-136 strongly inhibits the mitogenic effect of HARP on in vitro and in vivo growth of PC-3 cells. This inhibition could be linked to a direct or indirect binding of this peptide to the HARP receptors (ALK, RPTP�

Exosomes from heat-stressed tumour cells inhibit tumour growth by converting regulatory T cells to Th17 cells via IL-6.

PubMed

Guo, Danfeng; Chen, Yinghu; Wang, Shoujie; Yu, Lei; Shen, Yingying; Zhong, Haijun; Yang, Yunshan

2018-05-01

Exosomes derived from heat-stressed tumour cells (HS-TEXs), which contain abundant heat shock protein (HSP) 70, strongly induce antitumour immune responses. HSP70-induced interleukin (IL)-6 promotes IL-17 expression and causes rejection of established prostate tumours. However, it remains unclear whether HS-TEXs exhibit antitumour effects by converting regulatory T cells (T regs ) into T helper type 17 (Th17) cells. In this study, we found that compared with TEXs, HS-TEXs were more potent in stimulating secretion of IL-6 from dendritic cells. In vitro, IL-6 blocked tumour cell-derived transforming growth factor beta 1-induced T reg differentiation and promoted Th17 cell differentiation. HS-TEXs exerted strong antitumour effects, converting T regs into Th17 cells with high efficiency, a process that was entirely dependent upon IL-6. Neutralization of IL-17 completely abolished the antitumour effect of TEXs, but only partially inhibited that of HS-TEXs. In addition, we found higher levels of IL-6 and IL-17 in serum from tumour patients treated with hyperthermia, and an increase in Th17 cells and a decrease in T regs was detected in peripheral blood mononuclear cells isolated from these patients after hyperthermia. Therefore, our results demonstrate that HS-TEXs possess a powerful capacity to convert immunosuppressive T regs into Th17 cells via IL-6, which contributes to their potent antitumour effect. © 2017 John Wiley & Sons Ltd.

Selective uptake of single-walled carbon nanotubes by circulating monocytes for enhanced tumour delivery

NASA Astrophysics Data System (ADS)

Smith, Bryan Ronain; Ghosn, Eliver Eid Bou; Rallapalli, Harikrishna; Prescher, Jennifer A.; Larson, Timothy; Herzenberg, Leonore A.; Gambhir, Sanjiv Sam

2014-06-01

In cancer imaging, nanoparticle biodistribution is typically visualized in living subjects using `bulk' imaging modalities such as magnetic resonance imaging, computerized tomography and whole-body fluorescence. Accordingly, nanoparticle influx is observed only macroscopically, and the mechanisms by which they target cancer remain elusive. Nanoparticles are assumed to accumulate via several targeting mechanisms, particularly extravasation (leakage into tumour). Here, we show that, in addition to conventional nanoparticle-uptake mechanisms, single-walled carbon nanotubes are almost exclusively taken up by a single immune cell subset, Ly-6Chi monocytes (almost 100% uptake in Ly-6Chi monocytes, below 3% in all other circulating cells), and delivered to the tumour in mice. We also demonstrate that a targeting ligand (RGD) conjugated to nanotubes significantly enhances the number of single-walled carbon nanotube-loaded monocytes reaching the tumour (P < 0.001, day 7 post-injection). The remarkable selectivity of this tumour-targeting mechanism demonstrates an advanced immune-based delivery strategy for enhancing specific tumour delivery with substantial penetration.

Nanoparticles of Selaginella doederleinii leaf extract inhibit human lung cancer cells A549

NASA Astrophysics Data System (ADS)

Syaefudin; Juniarti, A.; Rosiyana, L.; Setyani, A.; Khodijah, S.

2016-01-01

The aim of the present study is to evaluate cytotoxicity effect of nanoparticles of Selaginella doederleinii (S. doederleinii) leaves extract. S. doederleinii was extracted by maceration method using 70%(v/v) ethanol as solvent. Phytochemical content was analyzed qualitatively by using Harborne and Thin Layer Chromatography (TLC) methods. Nanoparticle extract was prepared by ionic gelation using chitosan as encapsulant agent. Anticancer activity was performed by using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The results showed that S. doederleinii contains of flavonoids. Nanoparticle of S. doederleinii leaves extract greatly inhibited A549 cells growth (cancer cells), with IC50 of 3% or 1020 μg/ml. These nanoparticles extract also inhibited the growth of Chang cells (normal cells), with IC50 of 4% or 1442 μg/ml. The effective concentration of nanoparticles extract which inhibits cancer cells without harming the normal cells is 0.5% or 167 μg/ml. Further studies are needed to obtain the concentration of nanoparticles extract which can selectively suppress cancer cells.

Cholesteryl butyrate solid lipid nanoparticles inhibit the adhesion and migration of colon cancer cells

PubMed Central

Minelli, R; Serpe, L; Pettazzoni, P; Minero, V; Barrera, G; Gigliotti, CL; Mesturini, R; Rosa, AC; Gasco, P; Vivenza, N; Muntoni, E; Fantozzi, R; Dianzani, U; Zara, GP; Dianzani, C

2012-01-01

BACKGROUND AND PURPOSE Cholesteryl butyrate solid lipid nanoparticles (cholbut SLN) provide a delivery system for the anti-cancer drug butyrate. These SLN inhibit the adhesion of polymorphonuclear cells to the endothelium and may act as anti-inflammatory agents. As cancer cell adhesion to endothelium is crucial for metastasis dissemination, here we have evaluated the effect of cholbut SLN on adhesion and migration of cancer cells. EXPERIMENTAL APPROACH Cholbut SLN was incubated with a number of cancer cell lines or human umbilical vein endothelial cells (HUVEC) and adhesion was quantified by a computerized micro-imaging system. Migration was detected by the scratch ‘wound-healing’ assay and the Boyden chamber invasion assay. Expression of ERK and p38 MAPK was analysed by Western blot. Expression of the mRNA for E-cadherin and claudin-1 was measured by RT-PCR. KEY RESULTS Cholbut SLN inhibited HUVEC adhesiveness to cancer cell lines derived from human colon–rectum, breast, prostate cancers and melanoma. The effect was concentration and time-dependent and exerted on both cancer cells and HUVEC. Moreover, these SLN inhibited migration of cancer cells and substantially down-modulated ERK and p38 phosphorylation. The anti-adhesive effect was additive to that induced by the triggering of B7h, which is another stimulus inhibiting both ERK and p38 phosphorylation, and cell adhesiveness. Furthermore, cholbut SLN induced E-cadherin and inhibited claudin-1 expression in HUVEC. CONCLUSION AND IMPLICATIONS These results suggest that cholbut SLN could act as an anti-metastastic agent and they add a new mechanism to the anti-tumour activity of this multifaceted preparation of butyrate. PMID:22049973

Investigating inhibition of microbes inducing microbiologically-influenced-corrosion by Tectona grandis based Fe-nanoparticle material

NASA Astrophysics Data System (ADS)

Okeniyi, Joshua Olusegun; Omotosho, Olugbenga Adeshola; Inyang, Michael Anietie; Okeniyi, Elizabeth Toyin; Nwaokorie, Ikechi Thaddeus; Adidi, Emmanuel Amanogho; Owoeye, Taiwo Felicia; Nwakudu, Kelechukwu Chinedu; Akinlabu, Deborah Kehinde; Gabriel, Olanrewaju Oyewale; Taiwo, Olugbenga Samson; Awotoye, Olufisayo Adebola

2017-02-01

In this paper, inhibition of microbes inducing microbiologically-influenced-corrosion (MIC) of metals by Tectona grandis based Fe (iron) Nanoparticle material was investigated. For this, extract was obtained from the leaf of Tectona grandis and this was employed as precursor for synthesizing the Fe-nanoparticle material. From this, the synthesized plant extract based nanoparticle material was characterized using scanning electron microscopy and energy dispersive spectroscopy (SEM+EDS) instrument. The developed Fe bio-nanoparticle material was then employed for sensitivity and/or resistance study application against different strains of microbes that are known to induce microbiologically-influenced-corrosion, in metallic materials, and for this, microbial growth inhibition effect was compared with that from a commercial antibiotic employed as control. Results showed that the Tectona grandis based Fe-nanoparticle exhibited good inhibition effects on the growth of many of the MIC inducing microbes investigated. Sensitivity measures of zone of inhibition against the growth of MIC inducing microbial strains either outperformed or compares well with that obtained from the commercial antibiotic control, in the study. These results indicate positive prospect on the suitability of Fe bio-nanoparticle for corrosion inhibition applications for the protection of metals against microbiological corrosion influencing environment.

Magnetic particle hyperthermia—a promising tumour therapy?

NASA Astrophysics Data System (ADS)

Dutz, Silvio; Hergt, Rudolf

2014-11-01

We present a critical review of the state of the art of magnetic particle hyperthermia (MPH) as a minimal invasive tumour therapy. Magnetic principles of heating mechanisms are discussed with respect to the optimum choice of nanoparticle properties. In particular, the relation between superparamagnetic and ferrimagnetic single domain nanoparticles is clarified in order to choose the appropriate particle size distribution and the role of particle mobility for the relaxation path is discussed. Knowledge of the effect of particle properties for achieving high specific heating power provides necessary guidelines for development of nanoparticles tailored for tumour therapy. Nanoscale heat transfer processes are discussed with respect to the achievable temperature increase in cancer cells. The need to realize a well-controlled temperature distribution in tumour tissue represents the most serious problem of MPH, at present. Visionary concepts of particle administration, in particular by means of antibody targeting, are far from clinical practice, yet. On the basis of current knowledge of treating cancer by thermal damaging, this article elucidates possibilities, prospects, and challenges for establishment of MPH as a standard medical procedure.

Inhibition of indoleamine 2,3-dioxygenase activity enhances the anti-tumour effects of a Toll-like receptor 7 agonist in an established cancer model.

PubMed

Ito, Hiroyasu; Ando, Tatsuya; Arioka, Yuko; Saito, Kuniaki; Seishima, Mitsuru

2015-04-01

Toll-like receptor (TLR) agonists have been shown to have anti-tumour activity in basic research and clinical studies. However, TLR agonist monotherapy does not sufficiently eliminate tumours. Activation of the innate immune response by TLR agonists is effective at driving adaptive immunity via interleukin-12 (IL-12) or IL-1, but is counteracted by the simultaneous induction of immunosuppressive cytokines and other molecules, including IL-10, transforming growth factor-β, and indoleamine 2,3-dioxygenase (IDO). In the present study, we evaluated the anti-cancer effect of the TLR7 agonist, imiquimod (IMQ), in the absence of IDO activity. The administration of IMQ in IDO knockout (KO) mice inoculated with tumour cells significantly suppressed tumour progression compared with that in wild-type (WT) mice, and improved the survival rate. Moreover, injection with IMQ enhanced the tumour antigen-specific T helper type 1 response in IDO-KO mice with tumours. Combination therapy with IMQ and an IDO inhibitor also significantly inhibited tumour growth. Our results indicated that the enhancement of IDO expression with TLR agonists in cancer treatment might impair host anti-tumour immunity while the inhibition of IDO could enhance the therapeutic efficacy of TLR agonists via the increase of T helper type 1 immune response. © 2014 John Wiley & Sons Ltd.

Inhibition Effects of Silver Nanoparticles against Powdery Mildews on Cucumber and Pumpkin

PubMed Central

Lamsal, Kabir; Kim, Sang-Woo; Jung, Jin Hee; Kim, Yun Seok; Kim, Kyoung Su

2011-01-01

Powdery mildew is one of the most devastating diseases in cucurbits. Crop yield can decline as the disease severity increases. In this study, we evaluated the effect of silver nanoparticles against powdery mildew under different cultivation conditions in vitro and in vivo . Silver nanoparticles (WA-CV-WA13B) at various concentrations were applied before and after disease outbreak in plants to determine antifungal activities. In the field tests, the application of 100 ppm silver nanoparticles showed the highest inhibition rate for both before and after the outbreak of disease on cucumbers and pumpkins. Also, the application of 100 ppm silver nanoparticles showed maximum inhibition for the growth of fungal hyphae and conidial germination in in vivo tests. Scanning electron microscope results indicated that the silver nanoparticles caused detrimental effects on both mycelial growth and conidial germination. PMID:22783069

Inhibition Effects of Silver Nanoparticles against Powdery Mildews on Cucumber and Pumpkin.

PubMed

Lamsal, Kabir; Kim, Sang-Woo; Jung, Jin Hee; Kim, Yun Seok; Kim, Kyoung Su; Lee, Youn Su

2011-03-01

Powdery mildew is one of the most devastating diseases in cucurbits. Crop yield can decline as the disease severity increases. In this study, we evaluated the effect of silver nanoparticles against powdery mildew under different cultivation conditions in vitro and in vivo . Silver nanoparticles (WA-CV-WA13B) at various concentrations were applied before and after disease outbreak in plants to determine antifungal activities. In the field tests, the application of 100 ppm silver nanoparticles showed the highest inhibition rate for both before and after the outbreak of disease on cucumbers and pumpkins. Also, the application of 100 ppm silver nanoparticles showed maximum inhibition for the growth of fungal hyphae and conidial germination in in vivo tests. Scanning electron microscope results indicated that the silver nanoparticles caused detrimental effects on both mycelial growth and conidial germination.

Inhibition effect of engineered silver nanoparticles to bloom forming cyanobacteria

NASA Astrophysics Data System (ADS)

Thuy Duong, Thi; Son Le, Thanh; Thu Huong Tran, Thi; Kien Nguyen, Trung; Ho, Cuong Tu; Hien Dao, Trong; Phuong Quynh Le, Thi; Chau Nguyen, Hoai; Dang, Dinh Kim; Thu Huong Le, Thi; Thu Ha, Phuong

2016-09-01

Silver nanoparticle (AgNP) has a wide range antibacterial effect and is extensively used in different aspects of medicine, food storage, household products, disinfectants, biomonitoring and environmental remediation etc. In the present study, we examined the growth inhibition effect of engineered silver nanoparticles against bloom forming cyanobacterial M. aeruginosa strain. AgNPs were synthesized by a chemical reduction method at room temperature and UV-Vis spectroscopy, scanning electron microscopy (SEM), transmission electron microscope (TEM) showed that they presented a maximum absorption at 410 nm and size range between 10 and 18 nm. M. aeruginosa cells exposed during 10 d to AgNPs to a range of concentrations from 0 to 1 mg l-1. The changes in cell density and morphology were used to measure the responses of the M. aeruginosa to AgNPs. The control and treatment units had a significant difference in terms of cell density and growth inhibition (p < 0.05). Increasing the concentration of AgNPs, a reduction of the cell growths in all treatment was observed. The inhibition efficiency was reached 98.7% at higher concentration of AgNPs nanoparticles. The term half maximal effective concentration (EC50) based on the cell growth measured by absorbance at 680 nm (A680) was 0.0075 mg l-1. The inhibition efficiency was 98.7% at high concentration of AgNPs (1 mg l-1). Image of SEM and TEM reflected a shrunk and damaged cell wall indicating toxicity of silver nanoparticles toward M. aeruginosa.

PTK787/ZK222584, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, reduces uptake of the contrast agent GdDOTA by murine orthotopic B16/BL6 melanoma tumours and inhibits their growth in vivo.

PubMed

Rudin, Markus; McSheehy, Paul M J; Allegrini, Peter R; Rausch, Martin; Baumann, Diana; Becquet, Mike; Brecht, Karin; Brueggen, Josef; Ferretti, Stephane; Schaeffer, Fabienne; Schnell, Christian; Wood, Jeanette

2005-08-01

Assessment of tumour vascularity may characterize malignancy as well as predict responsiveness to anti-angiogenic therapy. Non-invasive measurement of tumour perfusion and blood vessel permeability assessed as the transfer constant, K(trans), can be provided by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Using the orthotopic murine tumour model B16/BL6 melanoma, the small contrast agent GdDOTA (DOTAREM(R); Guerbet, Paris) was applied to assess the vascular transfer constant, K(trans), and interstitial leakage space, whereas intravascular iron oxide nanoparticles (Endorem(R); Guerbet, Paris) were used to detect relative tumour blood volume (rTBV), and in one experiment blood flow index (BFI). No correlations were observed between these four parameters (r(2) always <0.05). The B16/BL6 primary tumour and lymph-node cervical (neck) metastases produced high levels of the permeability/growth factor, VEGF. To probe the model, the novel VEGF receptor (VEGF-R) tyrosine kinase inhibitor, PTK787/ZK222584 (PTK/ZK) was tested for anti-tumour efficacy and its effects on DCE-MRI measured parameters of tumour vascularity. Data from the non-invasive measure of tumour vascularity were compared with a histological measurement of vasculature using the DNA-staining dye H33342. PTK/ZK inhibited growth of the primary and, particularly, cervical tumour metastases following chronic treatment for 2 weeks (50 or 100 mg/kg daily) of 1-week-old tumours, or with 1 week of treatment against more established (2-week-old) tumours. After chronic treatment with PTK/ZK, DCE-MRI detected significant decreases in K(trans) and interstitial leakage space, but not rTBV of both primary tumours and cervical metastases. Histological data at this time-point showed a significant decrease in blood vessel density of the cervical metastases but not the primary tumours. However, in the cervical metastases, the mean blood vessel width was increased by 38%, suggesting overall no marked change in

Development of a Tumour Growth Inhibition Model to Elucidate the Effects of Ritonavir on Intratumoural Metabolism and Anti-tumour Effect of Docetaxel in a Mouse Model for Hereditary Breast Cancer.

PubMed

Yu, Huixin; Hendrikx, Jeroen J M A; Rottenberg, Sven; Schellens, Jan H M; Beijnen, Jos H; Huitema, Alwin D R

2016-03-01

In a mouse tumour model for hereditary breast cancer, we previously explored the anti-cancer effects of docetaxel, ritonavir and the combination of both and studied the effect of ritonavir on the intratumoural concentration of docetaxel. The objective of the current study was to apply pharmacokinetic (PK)-pharmacodynamic (PD) modelling on this previous study to further elucidate and quantify the effects of docetaxel when co-administered with ritonavir. PK models of docetaxel and ritonavir in plasma and in tumour were developed. The effect of ritonavir on docetaxel concentration in the systemic circulation of Cyp3a knock-out mice and in the implanted tumour (with inherent Cyp3a expression) was studied, respectively. Subsequently, we designed a tumour growth inhibition model that included the inhibitory effects of both docetaxel and ritonavir. Ritonavir decreased docetaxel systemic clearance with 8% (relative standard error 0.4%) in the co-treated group compared to that in the docetaxel only-treated group. The docetaxel concentration in tumour tissues was significantly increased by ritonavir with mean area under the concentration-time curve 2.5-fold higher when combined with ritonavir. Observed tumour volume profiles in mice could be properly described by the PK/PD model. In the co-treated group, the enhanced anti-tumour effect was mainly due to increased docetaxel tumour concentration; however, we demonstrated a small but significant anti-tumour effect of ritonavir addition (p value <0.001). In conclusion, we showed that the increased anti-tumour effect observed when docetaxel is combined with ritonavir is mainly caused by enhanced docetaxel tumour concentration and to a minor extent by a direct anti-tumour effect of ritonavir.

Anti-tumour strategies aiming to target tumour-associated macrophages

PubMed Central

Tang, Xiaoqiang; Mo, Chunfen; Wang, Yongsheng; Wei, Dandan; Xiao, Hengyi

2013-01-01

Tumour-associated macrophages (TAMs) represent a predominant population of inflammatory cells that present in solid tumours. TAMs are mostly characterized as alternatively activated M2-like macrophages and are known to orchestrate nearly all stages of tumour progression. Experimental investigations indicate that TAMs contribute to drug-resistance and radio-protective effects, and clinical evidence shows that an elevated number of TAMs and their M2 profile are correlated with therapy failure and poor prognosis in cancer patients. Recently, many studies on TAM-targeted strategies have made significant progress and some pilot works have achieved encouraging results. Among these, connections between some anti-tumour drugs and their influence on TAMs have been suggested. In this review, we will summarize recent advances in TAM-targeted strategies for tumour therapy. Based on the proposed mechanisms, those strategies are grouped into four categories: (i) inhibiting macrophage recruitment; (ii) suppressing TAM survival; (iii) enhancing M1-like tumoricidal activity of TAMs; (iv) blocking M2-like tumour-promoting activity of TAMs. It is desired that further attention be drawn to this research field and more effort be made to promote TAM-targeted tumour therapy. PMID:23113570

The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis.

PubMed

Nelson, Michaela; Yang, Ming; Dowle, Adam A; Thomas, Jerry R; Brackenbury, William J

2015-01-27

Voltage-gated Na(+) channels (VGSCs) are heteromeric protein complexes containing pore-forming α subunits and smaller, non-pore-forming β subunits. VGSCs are classically expressed in electrically excitable cells, e.g. neurons. VGSCs are also expressed in tumour cells, including breast cancer (BCa) cells, where they enhance cellular migration and invasion. However, despite extensive work defining in detail the molecular mechanisms underlying the expression of VGSCs and their pro-invasive role in cancer cells, there has been a notable lack of clinically relevant in vivo data exploring their value as potential therapeutic targets. We have previously reported that the VGSC-blocking antiepileptic drug phenytoin inhibits the migration and invasion of metastatic MDA-MB-231 cells in vitro. The purpose of the present study was to establish whether VGSCs might be viable therapeutic targets by testing the effect of phenytoin on tumour growth and metastasis in vivo. We found that expression of Nav1.5, previously detected in MDA-MB-231 cells in vitro, was retained on cells in orthotopic xenografts. Treatment with phenytoin, at a dose equivalent to that used to treat epilepsy (60 mg/kg; daily), significantly reduced tumour growth, without affecting animal weight. Phenytoin also reduced cancer cell proliferation in vivo and invasion into surrounding mammary tissue. Finally, phenytoin significantly reduced metastasis to the liver, lungs and spleen. This is the first study showing that phenytoin reduces breast tumour growth and metastasis in vivo. We propose that pharmacologically targeting VGSCs, by repurposing antiepileptic or antiarrhythmic drugs, should be further studied as a potentially novel anti-cancer therapy.

Aptamer-Conjugated Calcium Phosphate Nanoparticles for Reducing Diabetes Risk via Retinol Binding Protein 4 Inhibition.

PubMed

Torabi, Raheleh; Ghourchian, Hedayatollah; Amanlou, Massoud; Pasalar, Parvin

2017-06-01

Inhibition of the binding of retinol to its carrier, retinol binding protein 4, is a new strategy for treating type 2 diabetes; for this purpose, we have provided an aptamer-functionalized multishell calcium phosphate nanoparticle. First, calcium phosphate nanoparticles were synthesized and conjugated to the aptamer. The cytotoxicity of nanoparticles releases the process of aptamer from nanoparticles and their inhibition function of binding retinol to retinol binding protein 4. After synthesizing and characterizing the multishell calcium phosphate nanoparticles and observing the noncytotoxicity of conjugate, the optimum time (48 hours) and the pH (7.4) for releasing the aptamer from the nanoparticles was determined. The half-maximum inhibitory concentration (IC 50 ) value for inhibition of retinol binding to retinol binding protein 4 was 210 femtomolar (fmol). The results revealed that the aptamer could prevent connection between retinol and retinol binding protein 4 at a very low IC 50 value (210 fmol) compared to other reported inhibitors. It seems that this aptamer could be used as an efficient candidate not only for decreasing the insulin resistance in type 2 diabetes, but also for inhibiting the other retinol binding protein 4-related diseases. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

Engineered polymer nanoparticles containing hydrophobic dipeptide for inhibition of amyloid-β fibrillation.

PubMed

Skaat, Hadas; Chen, Ravit; Grinberg, Igor; Margel, Shlomo

2012-09-10

Protein aggregation into amyloid fibrils is implicated in the pathogenesis of many neurodegenerative diseases. Engineered nanoparticles have emerged as a potential approach to alter the kinetics of protein fibrillation process. Yet, there are only a few reports describing the use of nanoparticles for inhibition of amyloid-β 40 (Aβ(40)) peptide aggregation, involved in Alzheimer's disease (AD). In the present study, we designed new uniform biocompatible amino-acid-based polymer nanoparticles containing hydrophobic dipeptides in the polymer side chains. The dipeptide residues were designed similarly to the hydrophobic core sequence of Aβ. Poly(N-acryloyl-L-phenylalanyl-L-phenylalanine methyl ester) (polyA-FF-ME) nanoparticles of 57 ± 6 nm were synthesized by dispersion polymerization of the monomer A-FF-ME in 2-methoxy ethanol, followed by precipitation of the obtained polymer in aqueous solution. Cell viability assay confirmed that no significant cytotoxic effect of the polyA-FF-ME nanoparticles on different human cell lines, e.g., PC-12 and SH-SY5Y, was observed. A significantly slow secondary structure transition from random coil to β-sheets during Aβ(40) fibril formation was observed in the presence of these nanoparticles, resulting in significant inhibition of Aβ(40) fibrillation kinetics. However, the polyA-FF-ME analogous nanoparticles containing the L-alanyl-L-alanine (AA) dipeptide in the polymer side groups, polyA-AA-ME nanoparticles, accelerate the Aβ(40) fibrillation kinetics. The polyA-FF-ME nanoparticles and the polyA-AA-ME nanoparticles may therefore contribute to a mechanistic understanding of the fibrillation process, leading to the development of therapeutic strategies against amyloid-related diseases.

Tumour-specific delivery of siRNA-coupled superparamagnetic iron oxide nanoparticles, targeted against PLK1, stops progression of pancreatic cancer

PubMed Central

Mahajan, Ujjwal M; Teller, Steffen; Sendler, Matthias; Palankar, Raghavendra; van den Brandt, Cindy; Schwaiger, Theresa; Kühn, Jens-Peter; Ribback, Silvia; Glöckl, Gunnar; Evert, Matthias; Weitschies, Werner; Hosten, Norbert; Dombrowski, Frank; Delcea, Mihaela; Weiss, Frank-Ulrich; Lerch, Markus M; Mayerle, Julia

2016-01-01

Objective Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and is projected to be the second leading cause of cancer-related death by 2030. Despite extensive knowledge and insights into biological properties and genetic aberrations of PDAC, therapeutic options remain temporary and ineffective. One plausible explanation for the futile response to therapy is an insufficient and non-specific delivery of anticancer drugs to the tumour site. Design Superparamagnetic iron oxide nanoparticles (SPIONs) coupled with siRNA directed against the cell cycle-specific serine-threonine-kinase, Polo-like kinase-1 (siPLK1-StAv-SPIONs), could serve a dual purpose for delivery of siPLK1 to the tumour and for non-invasive assessment of efficiency of delivery in vivo by imaging the tumour response. siPLK1-StAv-SPIONs were designed and synthesised as theranostics to function via a membrane translocation peptide with added advantage of driving endosomal escape for mediating transportation to the cytoplasm (myristoylated polyarginine peptides) as well as a tumour-selective peptide (EPPT1) to increase intracellular delivery and tumour specificity, respectively. Results A syngeneic orthotopic as well as an endogenous cancer model was treated biweekly with siPLK1-StAv-SPIONs and tumour growth was monitored by small animal MRI. In vitro and in vivo experiments using a syngeneic orthotopic PDAC model as well as the endogenous LSL-KrasG12D, LSL-Trp53R172H, Pdx-1-Cre model revealed significant accumulation of siPLK1-StAv-SPIONs in PDAC, resulting in efficient PLK1 silencing. Tumour-specific silencing of PLK1 halted tumour growth, marked by a decrease in tumour cell proliferation and an increase in apoptosis. Conclusions Our data suggest siPLK1-StAv-SPIONs with dual specificity residues for tumour targeting and membrane translocation to represent an exciting opportunity for targeted therapy in patients with PDAC. PMID:27196585

Tumour-promoting phorbol esters increase basal and inhibit insulin-stimulated lipogenesis in rat adipocytes without decreasing insulin binding.

PubMed Central

van de Werve, G; Proietto, J; Jeanrenaud, B

1985-01-01

In isolated rat adipocytes, tumour-promoting phorbol esters caused (1) dose-dependent stimulation of lipogenesis in the absence of insulin and (2) inhibition of the lipogenic effect of submaximal concentrations of insulin, but without affecting insulin binding. The possible involvement of protein kinase C in insulin action is discussed. PMID:3883992

Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer.

PubMed

Murase, Ryuichi; Kawamura, Rumi; Singer, Eric; Pakdel, Arash; Sarma, Pranamee; Judkins, Jonathon; Elwakeel, Eiman; Dayal, Sonali; Martinez-Martinez, Esther; Amere, Mukkanti; Gujjar, Ramesh; Mahadevan, Anu; Desprez, Pierre-Yves; McAllister, Sean D

2014-10-01

The psychoactive cannabinoid Δ(9) -tetrahydrocannabinol (THC) and the non-psychoactive cannabinoid cannabidiol (CBD) can both reduce cancer progression, each through distinct anti-tumour pathways. Our goal was to discover a compound that could efficiently target both cannabinoid anti-tumour pathways. To measure breast cancer cell proliferation/viability and invasion, MTT and Boyden chamber assays were used. Modulation of reactive oxygen species (ROS) and apoptosis was measured using dichlorodihydrofluorescein and annexin/propidium iodide, respectively, in combination with cell flow cytometry. Changes in protein levels were evaluated using Western analysis. Orthotopic and i.v. mouse models of breast cancer metastasis were used to test the activity of cannabinoids in vivo. CBD reduced breast cancer metastasis in advanced stages of the disease as the direct result of down-regulating the transcriptional regulator Id1. However, this was associated with moderate increases in survival. We therefore screened for analogues that could co-target cannabinoid anti-tumour pathways (CBD- and THC-associated) and discovered the compound O-1663. This analogue inhibited Id1, produced a marked stimulation of ROS, up-regulated autophagy and induced apoptosis. Of all the compounds tested, it was the most potent at inhibiting breast cancer cell proliferation and invasion in culture and metastasis in vivo. O-1663 prolonged survival in advanced stages of breast cancer metastasis. Developing compounds that can simultaneously target multiple cannabinoid anti-tumour pathways efficiently may provide a novel approach for the treatment of patients with metastatic breast cancer. © 2014 The British Pharmacological Society.

Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer

PubMed Central

Murase, Ryuichi; Kawamura, Rumi; Singer, Eric; Pakdel, Arash; Sarma, Pranamee; Judkins, Jonathon; Elwakeel, Eiman; Dayal, Sonali; Martinez-Martinez, Esther; Amere, Mukkanti; Gujjar, Ramesh; Mahadevan, Anu; Desprez, Pierre-Yves; McAllister, Sean D

2014-01-01

Background and Purpose The psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) and the non-psychoactive cannabinoid cannabidiol (CBD) can both reduce cancer progression, each through distinct anti-tumour pathways. Our goal was to discover a compound that could efficiently target both cannabinoid anti-tumour pathways. Experimental Approach To measure breast cancer cell proliferation/viability and invasion, MTT and Boyden chamber assays were used. Modulation of reactive oxygen species (ROS) and apoptosis was measured using dichlorodihydrofluorescein and annexin/propidium iodide, respectively, in combination with cell flow cytometry. Changes in protein levels were evaluated using Western analysis. Orthotopic and i.v. mouse models of breast cancer metastasis were used to test the activity of cannabinoids in vivo. Key Results CBD reduced breast cancer metastasis in advanced stages of the disease as the direct result of down-regulating the transcriptional regulator Id1. However, this was associated with moderate increases in survival. We therefore screened for analogues that could co-target cannabinoid anti-tumour pathways (CBD- and THC-associated) and discovered the compound O-1663. This analogue inhibited Id1, produced a marked stimulation of ROS, up-regulated autophagy and induced apoptosis. Of all the compounds tested, it was the most potent at inhibiting breast cancer cell proliferation and invasion in culture and metastasis in vivo. Conclusions and Implications O-1663 prolonged survival in advanced stages of breast cancer metastasis. Developing compounds that can simultaneously target multiple cannabinoid anti-tumour pathways efficiently may provide a novel approach for the treatment of patients with metastatic breast cancer. PMID:24910342

Thrombin-inhibiting perfluorocarbon nanoparticles provide a novel strategy for treatment and magnetic resonance imaging of acute thrombosis

PubMed Central

Myerson, J.; He, L.; Lanza, G.; Tollefsen, D.; Wickline, S.

2013-01-01

Background As a regulator of the penultimate step in the coagulation cascade, thrombin represents a principal target of direct and specific anticoagulants. Objective A potent thrombin inhibitor complexed with a colloidal nanoparticle was devised as a first-in-class anticoagulant with prolonged and highly localized therapeutic impact conferred by its multivalent thrombin-absorbing particle surface. Methods PPACK (Phe(D)-Pro-Arg-Chloromethylketone) was secured covalently to the surface of perfluorocarbon-core nanoparticle structures. PPACK and PPACK nanoparticle inhibition of thrombin were assessed in vitro via thrombin activity against a chromogenic substrate. In vivo antithrombotic activity of PPACK, heparin, non-functionalized nanoparticles, and PPACK nanoparticles was assessed through IV administration prior to acute photochemical injury of the common carotid artery. Perfluorocarbon particle retention in extracted carotid arteries from injured mice was assessed via 19F magnetic resonance spectroscopy (MRS) and imaging (MRI) at 11.7 T. APTT measurements determined the systemic effects of the PPACK nanoparticles at various times after injection. Results Optical assay verified that PPACK nanoparticles exceeded PPACK’s intrinsic activity against thrombin. Application of the an in vivo acute arterial thrombosis model demonstrated that PPACK nanoparticles outperformed both heparin (p=.001) and uncomplexed PPACK (p=.0006) in inhibiting thrombosis. 19F MRS confirmed that PPACK nanoparticles specifically bound to sites of acute thrombotic injury. APTT normalized within twenty minutes of PPACK nanoparticles injection. Conclusions PPACK nanoparticles present thrombin-inhibiting surfaces at sites of acutely forming thrombi that continue to manifest local clot inhibition even as systemic effects rapidly diminish and thus represent a new platform for localized control of acute thrombosis. PMID:21605330

Efficient inhibition of EGFR signaling and of tumour growth by antagonistic anti-EFGR Nanobodies.

PubMed

Roovers, Rob C; Laeremans, Toon; Huang, Lieven; De Taeye, Severine; Verkleij, Arie J; Revets, Hilde; de Haard, Hans J; van Bergen en Henegouwen, Paul M P

2007-03-01

The development of a number of different solid tumours is associated with over-expression of ErbB1, or the epidermal growth factor receptor (EGFR), and this over-expression is often correlated with poor prognosis of patients. Therefore, this receptor tyrosine kinase is considered to be an attractive target for antibody-based therapy. Indeed, antibodies to the EGFR have already proven their value for the treatment of several solid tumours, especially in combination with chemotherapeutic treatment regimens. Variable domains of camelid heavy chain-only antibodies (called Nanobodies) have superior properties compared with classical antibodies in that they are small, very stable, easy to produce in large quantities and easy to re-format into multi-valent or multi-specific proteins. Furthermore, they can specifically be selected for a desired function by phage antibody display. In this report, we describe the successful selection and the characterisation of antagonistic anti-EGFR Nanobodies. By using a functional selection strategy, Nanobodies that specifically competed for EGF binding to the EGFR were isolated from "immune" phage Nanobody repertoires. The selected antibody fragments were found to efficiently inhibit EGF binding to the EGFR without acting as receptor agonists themselves. In addition, they blocked EGF-mediated signalling and EGF-induced cell proliferation. In an in vivo murine xenograft model, the Nanobodies were effective in delaying the outgrowth of A431-derived solid tumours. This is the first report describing the successful use of untagged Nanobodies for the in vivo treatment of solid tumours. The results show that functional phage antibody selection, coupled to the rational design of Nanobodies, permits the rapid development of novel anti-cancer antibody-based therapeutics.

Non-canonical NOTCH3 signalling limits tumour angiogenesis.

PubMed

Lin, Shuheng; Negulescu, Ana; Bulusu, Sirisha; Gibert, Benjamin; Delcros, Jean-Guy; Ducarouge, Benjamin; Rama, Nicolas; Gadot, Nicolas; Treilleux, Isabelle; Saintigny, Pierre; Meurette, Olivier; Mehlen, Patrick

2017-07-18

Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Here we describe an unexpected pro-apoptotic role of Notch3 in regulating tumour angiogenesis independently of the Notch canonical pathway. The Notch3 ligand Jagged-1 is upregulated in a fraction of human cancer and our data support the view that Jagged-1, produced by cancer cells, is inhibiting the apoptosis induced by the aberrant Notch3 expression in tumour vasculature. We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro-apoptotic activity is blocked by Jagged-1. Along this line, using Notch3 mutant mice, we demonstrate that tumour growth and angiogenesis are increased when Notch3 is silenced in the stroma. Consequently, we show that the well-documented anti-tumour effect mediated by γ-secretase inhibition is at least in part dependent on the apoptosis triggered by Notch3 in endothelial cells.

Non-canonical NOTCH3 signalling limits tumour angiogenesis

PubMed Central

Lin, Shuheng; Negulescu, Ana; Bulusu, Sirisha; Gibert, Benjamin; Delcros, Jean-Guy; Ducarouge, Benjamin; Rama, Nicolas; Gadot, Nicolas; Treilleux, Isabelle; Saintigny, Pierre; Meurette, Olivier; Mehlen, Patrick

2017-01-01

Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Here we describe an unexpected pro-apoptotic role of Notch3 in regulating tumour angiogenesis independently of the Notch canonical pathway. The Notch3 ligand Jagged-1 is upregulated in a fraction of human cancer and our data support the view that Jagged-1, produced by cancer cells, is inhibiting the apoptosis induced by the aberrant Notch3 expression in tumour vasculature. We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro-apoptotic activity is blocked by Jagged-1. Along this line, using Notch3 mutant mice, we demonstrate that tumour growth and angiogenesis are increased when Notch3 is silenced in the stroma. Consequently, we show that the well-documented anti-tumour effect mediated by γ-secretase inhibition is at least in part dependent on the apoptosis triggered by Notch3 in endothelial cells. PMID:28719575

Second Generation Amphiphilic Poly-Lysine Dendrons Inhibit Glioblastoma Cell Proliferation without Toxicity for Neurons or Astrocytes

PubMed Central

Janiszewska, Jolanta; Posadas, Inmaculada; Játiva, Pablo; Bugaj-Zarebska, Marta; Urbanczyk-Lipkowska, Zofia; Ceña, Valentín

2016-01-01

Glioblastomas are the most common malignant primary brain tumours in adults and one of the most aggressive and difficult-to-treat cancers. No effective treatment exits actually for this tumour and new therapeutic approaches are needed for this disease. One possible innovative approach involves the nanoparticle-mediated specific delivery of drugs and/or genetic material to glioblastoma cells where they can provide therapeutic benefits. In the present work, we have synthesised and characterised several second generation amphiphilic polylysine dendrons to be used as siRNA carriers. We have found that, in addition to their siRNA binding properties, these new compounds inhibit the proliferation of two glioblastoma cell lines while being nontoxic for non-tumoural central nervous system cells like neurons and glia, cell types that share the anatomical space with glioblastoma cells during the course of the disease. The selective toxicity of these nanoparticles to glioblastoma cells, as compared to neurons and glial cells, involves mitochondrial depolarisation and reactive oxygen species production. This selective toxicity, together with the ability to complex and release siRNA, suggests that these new polylysine dendrons might offer a scaffold in the development of future nanoparticles designed to restrict the proliferation of glioblastoma cells. PMID:27832093

Synthetically lethal nanoparticles for treatment of endometrial cancer

NASA Astrophysics Data System (ADS)

Ebeid, Kareem; Meng, Xiangbing; Thiel, Kristina W.; Do, Anh-Vu; Geary, Sean M.; Morris, Angie S.; Pham, Erica L.; Wongrakpanich, Amaraporn; Chhonker, Yashpal S.; Murry, Daryl J.; Leslie, Kimberly K.; Salem, Aliasger K.

2018-01-01

Uterine serous carcinoma, one of the most aggressive types of endometrial cancer, is characterized by poor outcomes and mutations in the tumour suppressor p53. Our objective was to engender synthetic lethality to paclitaxel (PTX), the frontline treatment for endometrial cancer, in tumours with mutant p53 and enhance the therapeutic efficacy using polymeric nanoparticles (NPs). First, we identified the optimal NP formulation through comprehensive analyses of release profiles and cellular-uptake and cell viability studies. Not only were PTX-loaded NPs superior to PTX in solution, but the combination of PTX-loaded NPs with the antiangiogenic molecular inhibitor BIBF 1120 (BIBF) promoted synthetic lethality specifically in cells with the loss-of-function (LOF) p53 mutation. In a xenograft model of endometrial cancer, this combinatorial therapy resulted in a marked inhibition of tumour progression and extended survival. Together, our data provide compelling evidence for future studies of BIBF- and PTX-loaded NPs as a therapeutic opportunity for LOF p53 cancers.

Imatinib Mesylate Exerts Anti-Proliferative Effects on Osteosarcoma Cells and Inhibits the Tumour Growth in Immunocompetent Murine Models

PubMed Central

Ory, Benjamin; Charrier, Céline; Brion, Régis; Blanchard, Frederic; Redini, Françoise; Heymann, Dominique

2014-01-01

Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma), a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1). Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma) and POS-1 (undifferentiated osteosarcoma). Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R), appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor status of patients

Bismuth oxide aqueous colloidal nanoparticles inhibit Candida albicans growth and biofilm formation

PubMed Central

Hernandez-Delgadillo, Rene; Velasco-Arias, Donaji; Martinez-Sanmiguel, Juan Jose; Diaz, David; Zumeta-Dube, Inti; Arevalo-Niño, Katiushka; Cabral-Romero, Claudio

2013-01-01

Multiresistance among microorganisms to common antimicrobials has become one of the most significant concerns in modern medicine. Nanomaterials are a new alternative to successfully treat the multiresistant microorganisms. Nanostructured materials are used in many fields, including biological sciences and medicine. Recently, it was demonstrated that the bactericidal activity of zero-valent bismuth colloidal nanoparticles inhibited the growth of Streptococcus mutans; however the antimycotic potential of bismuth nanostructured derivatives has not yet been studied. The main objective of this investigation was to analyze the fungicidal activity of bismuth oxide nanoparticles against Candida albicans, and their antibiofilm capabilities. Our results showed that aqueous colloidal bismuth oxide nanoparticles displayed antimicrobial activity against C. albicans growth (reducing colony size by 85%) and a complete inhibition of biofilm formation. These results are better than those obtained with chlorhexidine, nystatin, and terbinafine, the most effective oral antiseptic and commercial antifungal agents. In this work, we also compared the antimycotic activities of bulk bismuth oxide and bismuth nitrate, the precursor metallic salt. These results suggest that bismuth oxide colloidal nanoparticles could be a very interesting candidate as a fungicidal agent to be incorporated into an oral antiseptic. Additionally, we determined the minimum inhibitory concentration for the synthesized aqueous colloidal Bi2O3 nanoparticles. PMID:23637533

Thrombin-inhibiting nanoparticles rapidly constitute versatile and detectable anticlotting surfaces

NASA Astrophysics Data System (ADS)

Wheatley Myerson, Jacob; He, Li; Allen, John Stacy; Williams, Todd; Lanza, Gregory; Tollefsen, Douglas; Caruthers, Shelton; Wickline, Samuel

2014-09-01

Restoring an antithrombotic surface to suppress ongoing thrombosis is an appealing strategy for treatment of acute cardiovascular disorders such as erosion of atherosclerotic plaque. An antithrombotic surface would present an alternative to systemic anticoagulation with attendant risks of bleeding. We have designed thrombin-targeted nanoparticles (NPs) that bind to sites of active clotting to extinguish local thrombin activity and inhibit platelet deposition while exhibiting only transient systemic anticoagulant effects. Perfluorocarbon nanoparticles (PFC NP) were functionalized with thrombin inhibitors (either D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone or bivalirudin) by covalent attachment of more than 15 000 inhibitors to each PFC NP. Fibrinopeptide A (FPA) ELISA demonstrated that thrombin-inhibiting NPs prevented cleavage of fibrinogen by both free and clot-bound thrombin. Magnetic resonance imaging (MRI) confirmed that a layer of thrombin-inhibiting NPs prevented growth of clots in vitro. Thrombin-inhibiting NPs were administered in vivo to C57BL6 mice subjected to laser injury of the carotid artery. NPs significantly delayed thrombotic occlusion of the artery, whereas an equivalent bolus of free inhibitor was ineffective. For thrombin-inhibiting NPs, only a short-lived (˜10 min) systemic effect on bleeding time was observed, despite prolonged clot inhibition. Imaging and quantification of in vivo antithrombotic NP layers was demonstrated by MRI of the PFC NP. 19F MRI confirmed colocalization of particles with arterial thrombi, and quantitative 19F spectroscopy demonstrated specific binding and retention of thrombin-inhibiting NPs in injured arteries. The ability to rapidly form and image a new antithrombotic surface in acute vascular syndromes while minimizing risks of bleeding would permit a safer method of passivating active lesions than current systemic anticoagulant regimes.

The anti-tumour effects of zoledronic acid

PubMed Central

Zekri, Jamal; Mansour, Maged; Karim, Syed Mustafa

2014-01-01

Bone is the most common site for metastasis in patients with solid tumours. Bisphosphonates are an effective treatment for preventing skeletal related events and preserving quality of life in these patients. Zoledronic acid (ZA) is the most potent osteoclast inhibitor and is licensed for the treatment of bone metastases. Clodronate and pamidronate are also licensed for this indication. In addition, ZA has been demonstrated to exhibit antitumour effect. Direct and indirect mechanisms of anti-tumour effect have been postulated and at many times proven. Evidence exists that ZA antitumour effect is mediated through inhibition of tumour cells proliferation, induction of apoptosis, synergistic/additive to inhibitory effect of cytotoxic agents, inhibition of angiogenesis, decrease tumour cells adhesion to bone, decrease tumour cells invasion and migration, disorganization of cell cytoskeleton and activation of specific cellular antitumour immune response. There is also clinical evidence from clinical trials that ZA improved long term survival outcome in cancer patients with and without bone metastases. In this review we highlight the preclinical and clinical studies investigating the antitumour effect of bisphosphonates with particular reference to ZA. PMID:26909294

Deoxyschizandrin, Isolated from Schisandra Berries, Induces Cell Cycle Arrest in Ovarian Cancer Cells and Inhibits the Protumoural Activation of Tumour-Associated Macrophages.

PubMed

Lee, Kijun; Ahn, Ji-Hye; Lee, Kyung-Tae; Jang, Dae Sik; Choi, Jung-Hye

2018-01-15

Deoxyschizandrin, a major lignan of Schisandra berries, has been demonstrated to have various biological activities such as antioxidant, hepatoprotective, and antidiabetic effects. However, the anti-cancer effects of deoxyschizandrin are poorly characterized. In the present study, we investigated the anti-cancer effect of deoxyschizandrin on human ovarian cancer cell lines and tumour-associated macrophages (TAMs). Deoxyschizandrin induced G₀/G₁ phase cell cycle arrest and inhibited cyclin E expression in human ovarian cancer cells. Overexpression of cyclin E significantly reversed the deoxyschizandrin-induced cell growth inhibition. Interestingly, increased production of reactive oxygen species and decreased activation of Akt were observed in A2780 cells treated with deoxyschizandrin, and the antioxidant compromised the deoxyschizandrin-induced cell growth inhibition and Akt inactivation. Moreover, deoxyschizandrin-induced cell growth inhibition was markedly suppressed by Akt overexpression. In addition, deoxyschizandrin was found to inhibit the expression of the M2 phenotype markers CD163 and CD209 in TAMs, macrophages stimulated by the ovarian cancer cells. Moreover, expression and production of the tumour-promoting factors MMP-9, RANTES, and VEGF, which are highly enhanced in TAMs, was significantly suppressed by deoxyschizandrin treatment. Taken together, these data suggest that deoxyschizandrin exerts anti-cancer effects by inducing G₀/G₁ cell cycle arrest in ovarian cancer cells and reducing the protumoural phenotype of TAMs.

In Vitro and in Vivo Mechanism of Bone Tumor Inhibition by Selenium-Doped Bone Mineral Nanoparticles.

PubMed

Wang, Yifan; Wang, Jianglin; Hao, Hang; Cai, Mingle; Wang, Shiyao; Ma, Jun; Li, Yan; Mao, Chuanbin; Zhang, Shengmin

2016-11-22

Biocompatible tissue-borne crystalline nanoparticles releasing anticancer therapeutic inorganic elements are intriguing therapeutics holding the promise for both tissue repair and cancer therapy. However, how the therapeutic inorganic elements released from the lattice of such nanoparticles induce tumor inhibition remains unclear. Here we use selenium-doped hydroxyapatite nanoparticles (Se-HANs), which could potentially fill the bone defect generated from bone tumor removal while killing residual tumor cells, as an example to study the mechanism by which selenium released from the lattice of Se-HANs induces apoptosis of bone cancer cells in vitro and inhibits the growth of bone tumors in vivo. We found that Se-HANs induced apoptosis of tumor cells by an inherent caspase-dependent apoptosis pathway synergistically orchestrated with the generation of reactive oxygen species. Such mechanism was further validated by in vivo animal evaluation in which Se-HANs tremendously induced tumor apoptosis to inhibit tumor growth while reducing systemic toxicity. Our work proposes a feasible paradigm toward the design of tissue-repairing inorganic nanoparticles that bear therapeutic ions in the lattice and can release them in vivo for inhibiting tumor formation.

A Preliminary Assessment of Silver Nanoparticle Inhibition of Monkeypox Virus Plaque Formation

NASA Astrophysics Data System (ADS)

Rogers, James V.; Parkinson, Christopher V.; Choi, Young W.; Speshock, Janice L.; Hussain, Saber M.

2008-04-01

The use of nanotechnology and nanomaterials in medical research is growing. Silver-containing nanoparticles have previously demonstrated antimicrobial efficacy against bacteria and viral particles. This preliminary study utilized an in vitro approach to evaluate the ability of silver-based nanoparticles to inhibit infectivity of the biological select agent, monkeypox virus (MPV). Nanoparticles (10 80 nm, with or without polysaccharide coating), or silver nitrate (AgNO3) at concentrations of 100, 50, 25, and 12.5 μg/mL were evaluated for efficacy using a plaque reduction assay. Both Ag-PS-25 (polysaccharide-coated, 25 nm) and Ag-NP-55 (non-coated, 55 nm) exhibited a significant ( P ≤ 0.05) dose-dependent effect of test compound concentration on the mean number of plaque-forming units (PFU). All concentrations of silver nitrate (except 100 μg/mL) and Ag-PS-10 promoted significant ( P ≤ 0.05) decreases in the number of observed PFU compared to untreated controls. Some nanoparticle treatments led to increased MPV PFU ranging from 1.04- to 1.8-fold above controls. No cytotoxicity (Vero cell monolayer sloughing) was caused by any test compound, except 100 μg/mL AgNO3. These results demonstrate that silver-based nanoparticles of approximately 10 nm inhibit MPV infection in vitro, supporting their potential use as an anti-viral therapeutic.

Can small hydrophobic gold nanoparticles inhibit β2-microglobulin fibrillation?

NASA Astrophysics Data System (ADS)

Brancolini, Giorgia; Toroz, Dimitrios; Corni, Stefano

2014-06-01

Inorganic nanoparticles stabilized by a shell of organic ligands can enhance or suppress the natural propensity of proteins to form fibrils. Functionalization facilitates targeted delivery of the nanoparticles to various cell types, bioimaging, drug delivery and other therapeutic and diagnostic applications. In this study, we provide a computational model of the effect of a prototypical thiol-protected gold nanoparticle, Au25L18- (L = S(CH2)2Ph) on the β2-microglobulin natural fibrillation propensity. To reveal the molecular basis of the protein-nanoparticle association process, we performed various simulations at multiple levels (Classical Molecular Dynamics and Brownian Dynamics) that cover multiple length- and timescales. The results provide a model of the ensemble of structures constituting the protein-gold nanoparticle complexes, and insights into the driving forces for the binding of β2-microglobulin to hydrophobic small size gold nanoparticles. We have found that the small nanoparticles can bind the protein to form persistent complexes. This binding of nanoparticles is able to block the active sites of domains from binding to another protein, thus leading to potential inhibition of the fibrillation activity. A comparison with the binding patches identified for the interaction of the protein with a known inhibitor of fibrillation, supports our conclusion.Inorganic nanoparticles stabilized by a shell of organic ligands can enhance or suppress the natural propensity of proteins to form fibrils. Functionalization facilitates targeted delivery of the nanoparticles to various cell types, bioimaging, drug delivery and other therapeutic and diagnostic applications. In this study, we provide a computational model of the effect of a prototypical thiol-protected gold nanoparticle, Au25L18- (L = S(CH2)2Ph) on the β2-microglobulin natural fibrillation propensity. To reveal the molecular basis of the protein-nanoparticle association process, we performed various

Nanoparticle-triggered in situ catalytic chemical reactions for tumour-specific therapy.

PubMed

Lin, Han; Chen, Yu; Shi, Jianlin

2018-03-21

Tumour chemotherapy employs highly cytotoxic chemodrugs, which kill both cancer and normal cells by cellular apoptosis or necrosis non-selectively. Catalysing/triggering the specific chemical reactions only inside tumour tissues can generate abundant and special chemicals and products locally to initiate a series of unique biological and pathologic effects, which may enable tumour-specific theranostic effects to combat cancer without bringing about significant side effects on normal tissues. Nevertheless, chemical reaction-initiated selective tumour therapy strongly depends on the advances in chemistry, materials science, nanotechnology and biomedicine. This emerging cross-disciplinary research area is substantially different from conventional cancer-theranostic modalities in clinics. In response to the fast developments in cancer theranostics based on intratumoural catalytic chemical reactions, this tutorial review summarizes the very-recent research progress in the design and synthesis of representative nanoplatforms with intriguing nanostructures, compositions, physiochemical properties and biological behaviours for versatile catalytic chemical reaction-enabled cancer treatments, mainly by either endogenous tumour microenvironment (TME) triggering or exogenous physical irradiation. These unique intratumoural chemical reactions can be used in tumour-starving therapy, chemodynamic therapy, gas therapy, alleviation of tumour hypoxia, TME-responsive diagnostic imaging and stimuli-responsive drug release, and even externally triggered versatile therapeutics. In particular, the challenges and future developments of such a novel type of cancer-theranostic modality are discussed in detail to understand the future developments and prospects in this research area as far as possible. It is highly expected that this kind of unique tumour-specific therapeutics by triggering specific in situ catalytic chemical reactions inside tumours would provide a novel but efficient

miR-188-5p inhibits tumour growth and metastasis in prostate cancer by repressing LAPTM4B expression

PubMed Central

Zhang, Hongtuan; Qi, Shiyong; Zhang, Tao; Wang, Andi; Liu, Ranlu; Guo, Jia; Wang, Yuzhuo; Xu, Yong

2015-01-01

Elucidation of the molecular targets and pathways regulated by the tumour-suppressive miRNAs can shed light on the oncogenic and metastatic processes in prostate cancer (PCa). Using miRNA profiling analysis, we find that miR-188-5p was significantly down-regulated in metastatic PCa. Down-regulation of miR-188-5p is an independent prognostic factor for poor overall and biochemical recurrence-free survival. Restoration of miR-188-5p in PCa cells (PC-3 and LNCaP) significantly suppresses proliferation, migration and invasion in vitro and inhibits tumour growth and metastasis in vivo. We also find overexpression of miR-188-5p in PC-3 cells can significantly enhance the cells' chemosensitivity to adriamycin. LAPTM4B is subsequently identified as a direct target of miR-188-5p in PCa, and is found to be significantly over-expressed in PCa. Knockdown of LAPTM4B phenotypically copies miR-188-5p-induced phenotypes, whereas ectopic expression of LAPTM4B reverses the effects of miR-188-5p. We also find that restoration of miR-188-5p can inhibit the PI3K/AKT signaling pathway via the suppression of LAPTM4B. Taken together, this is the first report unveils that miR-188-5p acts as a tumour suppressor in PCa and may therefore serve as a useful therapeutic target for the development of new anticancer therapy. PMID:25714029

miR-188-5p inhibits tumour growth and metastasis in prostate cancer by repressing LAPTM4B expression.

PubMed

Zhang, Hongtuan; Qi, Shiyong; Zhang, Tao; Wang, Andi; Liu, Ranlu; Guo, Jia; Wang, Yuzhuo; Xu, Yong

2015-03-20

Elucidation of the molecular targets and pathways regulated by the tumour-suppressive miRNAs can shed light on the oncogenic and metastatic processes in prostate cancer (PCa). Using miRNA profiling analysis, we find that miR-188-5p was significantly down-regulated in metastatic PCa. Down-regulation of miR-188-5p is an independent prognostic factor for poor overall and biochemical recurrence-free survival. Restoration of miR-188-5p in PCa cells (PC-3 and LNCaP) significantly suppresses proliferation, migration and invasion in vitro and inhibits tumour growth and metastasis in vivo. We also find overexpression of miR-188-5p in PC-3 cells can significantly enhance the cells' chemosensitivity to adriamycin. LAPTM4B is subsequently identified as a direct target of miR-188-5p in PCa, and is found to be significantly over-expressed in PCa. Knockdown of LAPTM4B phenotypically copies miR-188-5p-induced phenotypes, whereas ectopic expression of LAPTM4B reverses the effects of miR-188-5p. We also find that restoration of miR-188-5p can inhibit the PI3K/AKT signaling pathway via the suppression of LAPTM4B. Taken together, this is the first report unveils that miR-188-5p acts as a tumour suppressor in PCa and may therefore serve as a useful therapeutic target for the development of new anticancer therapy.

Tumour related inhibition of macrophage chemotaxis in patients with colon cancer.

PubMed Central

Hermanowicz, A; Gibson, P R; Jewell, D P

1987-01-01

The chemotactic migration in vitro of peripheral blood, intestinal mucosal, and mesenteric lymph node mononuclear cells has been assessed in patients with colorectal carcinoma. Peripheral blood mononuclear cells of patients exhibited normal chemotaxis. For control patients with non-malignant, non-inflammatory intestinal disease, the chemotaxis of mucosal mononuclear cells was similar to that of autologous peripheral blood mononuclear cells. The chemotactic migration of mucosal mononuclear cells, however, isolated distant from a colon cancer was less than that of autologous peripheral blood mononuclear cells. Chemotactic migration was progressively impaired with increasing closeness to the tumour itself. Chemotaxis of mucosal mononuclear cell was independent of the site of tumour and the Dukes' grading. Mononuclear cells from mesenteric lymph nodes, however, exhibited impaired migration only in patients with Dukes' C tumours. Supernatants of the collagenase digestion of either tumour or adjacent mucosa contained macrophage directed inhibitors of chemotaxis and these inhibitors were not produced by tumour mononuclear cells. The presence of such inhibitors in the digestion supernatants and the demonstration that proximity to the tumour was associated with impaired mononuclear cell motility suggest that the production of macrophage directed chemotactic inhibitors is by colon cancer cells and that this may be occurring in vivo. PMID:3583069

Inhibition of purine phosphoribosyltransferases of Ehrlich ascites-tumour cells by 6-mercaptopurine

PubMed Central

Atkinson, M. R.; Murray, A. W.

1965-01-01

1. The formation of adenosine 5′-phosphate, guanosine 5′-phosphate and inosine 5′-phosphate from [8-14C]adenine, [8-14C]guanine and [8-14C]hypoxanthine respectively in the presence of 5-phosphoribosyl pyrophosphate and an extract from Ehrlich ascites-tumour cells was assayed by a method involving liquid-scintillation counting of the radioactive nucleotides on diethylaminoethylcellulose paper. The results obtained with guanine were confirmed by a spectrophotometric assay which was also used to assay the conversion of 6-mercaptopurine and 5-phosphoribosyl pyrophosphate into 6-thioinosine 5′-phosphate in the presence of 6-mercaptopurine phosphoribosyltransferase from these cells. 2. At pH 7·8 and 25° the Michaelis constants for adenine, guanine and hypoxanthine were 0·9 μm, 2·9 μm and 11·0 μm in the assay with radioactive purines; the Michaelis constant for guanine in the spectrophotometric assay was 2·6 μm. At pH 7·9 the Michaelis constant for 6-mercaptopurine was 10·9 μm. 3. 25 μm-6-Mercaptopurine did not inhibit adenine phosphoribosyltransferase. 6-Mercaptopurine is a competitive inhibitor of guanine phosphoribosyltransferase (Ki 4·7 μm) and hypoxanthine phosphoribosyltransferase (Ki 8·3 μm). Hypoxanthine is a competitive inhibitor of guanine phosphoribosyltransferase (Ki 3·4 μm). 4. Differences in kinetic parameters and in the distribution of phosphoribosyltransferase activities after electrophoresis in starch gel indicate that different enzymes are involved in the conversion of adenine, guanine and hypoxanthine into their nucleotides. 5. From the low values of Ki for 6-mercaptopurine, and from published evidence that ascites-tumour cells require supplies of purines from the host tissues, it is likely that inhibition of hypoxanthine and guanine phosphoribosyltransferases by free 6-mercaptopurine is involved in the biological activity of this drug. PMID:14342250

JS-K has potent anti-angiogenic activity in vitro and inhibits tumour angiogenesis in a multiple myeloma model in vivo.

PubMed

Kiziltepe, Tanyel; Anderson, Kenneth C; Kutok, Jeffery L; Jia, Lee; Boucher, Kenneth M; Saavedra, Joseph E; Keefer, Larry K; Shami, Paul J

2010-01-01

Glutathione S-transferases (GSTs) play an important role in multidrug resistance and are upregulated in multiple cancers. We have designed a prodrug class that releases nitric oxide on metabolism by GST. O(2)-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent antineoplastic activity. We studied the effect of JS-K on angiogenesis in human umbilical vein endothelial cells (HUVECs), OPM1 multiple myeloma cells, chick aortic rings and in mice. JS-K inhibited the proliferation of HUVECs with a 50% inhibitory concentration (IC50) of 0.432, 0.466 and 0.505 microm at 24, 48 and 72 h, respectively. In the cord formation assay, JS-K led to a decrease in the number of cord junctions and cord length with an IC50 of 0.637 and 0.696 microm, respectively. JS-K inhibited cell migration at 5 h using VEGF as a chemoattractant. Migration inhibition occurred with an IC50 of 0.493 microm. In the chick aortic ring assay using VEGF or FGF-2 for vessel growth stimulation, 0.5 microm JS-K completely inhibited vessel growth. JS-K inhibited tumour angiogenesis in vivo in NIH III mice implanted subcutaneously with OPM1 multiple myeloma cells. JS-K is a potent inhibitor of angiogenesis in vitro and tumour vessel growth in vivo. As such, it establishes a new class of antineoplastic agent that targets the malignant cells directly as well as their microenvironment.

Matrix metalloproteases inhibition and biocompatibility of gold and platinum nanoparticles.

PubMed

Hashimoto, Masanori; Kawai, Koji; Kawakami, Hayato; Imazato, Satoshi

2016-01-01

Matrix metalloprotease (MMP) inhibitors improve the longevity of dental adhesives/tooth bonds; however, biocompatibility is required for their clinical use. This study evaluated the inhibition of MMPs and toxicity of two gold (AuNPs) and platinum nanoparticles (PtNPs) as possible compounds for use in dental adhesives. The MMP assay for studying the interaction of MMPs and nanoparticles (NPs) was evaluated by an MMP assay kit and gelatin zymography. Cultured L929 fibroblast cells or RAW264 macrophages were exposed to NPs. The cellular responses to NPs were examined using cytotoxic (cell viability) and genotoxic assays (comet assay), and transmission electron microscopic (TEM) analysis. The mechanical properties (elastic modulus) of the experimental resin loaded with NPs were examined using thermomechanical analysis. All NPs inhibited MMP activity at relatively low concentrations. The NPs inhibit MMPs by chelating with the Zn(2+) bound in the active sites of MMPs. No cytotoxic and genotoxic effects were found in AuNPs, whereas the PtNPs possessed both adverse effects. In TEM analysis, the NPs were localized mainly in lysosomes without penetration into nuclei. The mechanical properties of the resins increased when AuNPs were added in resins, but not by PtNPs. AuNPs are attractive candidates to inhibit MMPs and improve the mechanical properties of resins without cytotoxic/genotoxic effects to cells, and therefore should be suitable for applications in adhesive resin systems. © 2015 Wiley Periodicals, Inc.

Genetically engineered and self-assembled oncolytic protein nanoparticles for targeted cancer therapy.

PubMed

Lee, Joong-Jae; Kang, Jung Ae; Ryu, Yiseul; Han, Sang-Soo; Nam, You Ree; Rho, Jong Kook; Choi, Dae Seong; Kang, Sun-Woong; Lee, Dong-Eun; Kim, Hak-Sung

2017-03-01

The integration of a targeted delivery with a tumour-selective agent has been considered an ideal platform for achieving high therapeutic efficacy and negligible side effects in cancer therapy. Here, we present engineered protein nanoparticles comprising a tumour-selective oncolytic protein and a targeting moiety as a new format for the targeted cancer therapy. Apoptin from chicken anaemia virus (CAV) was used as a tumour-selective apoptotic protein. An EGFR-specific repebody, which is composed of LRR (Leucine-rich repeat) modules, was employed to play a dual role as a tumour-targeting moiety and a fusion partner for producing apoptin nanoparticles in E. coli, respectively. The repebody was genetically fused to apoptin, and the resulting fusion protein was shown to self-assemble into supramolecular repebody-apoptin nanoparticles with high homogeneity and stability as a soluble form when expressed in E. coli. The repebody-apoptin nanoparticles showed a remarkable anti-tumour activity with negligible side effects in xenograft mice through a cooperative action of the two protein components with distinct functional roles. The repebody-apoptin nanoparticles can be developed as a systemic injectable and tumour-selective therapeutic protein for targeted cancer treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Inhibitory effect of magnolol on tumour metastasis in mice.

PubMed

Ikeda, Koji; Sakai, Yoshimichi; Nagase, Hisamitsu

2003-09-01

It has previously been reported that magnolol, a phenolic compound isolated from Magnolia obovata, inhibited tumour cell invasion in vitro. The purpose of this study was to investigate the antimetastatic effect of magnolol on tumour metastasis in vivo with experimental and spontaneous metastasis models and to clarify the mechanism. The antimetastatic effects of magnolol were evaluated by an experimental liver and spleen metastasis model using L5178Y-ML25 lymphoma, or an experimental and spontaneous lung metastasis model using B16-BL6 melanoma. Intraperitoneal (i.p.) administration of 2 or 10 mg/kg of magnolol significantly suppressed liver and spleen metastasis or lung metastasis. As for the spontaneous lung metastasis model using B16-BL6 melanoma, multiple i.p. administrations of 10 mg/kg of magnolol after and before tumour inoculation significantly suppressed lung metastasis and primary tumour growth. In addition, magnolol significantly inhibited B16-BL6 cell invasion of the reconstituted basement membrane (Matrigel, MG) without affecting cell growth. These data from the in vivo experiments suggest that magnolol possesses strong antimetastatic ability and that it may be a lead compound for drug development. The antimetastatic action of magnolol is considered to be due to its ability to inhibit tumour cell invasion. Copyright 2003 John Wiley & Sons, Ltd.

Zerovalent bismuth nanoparticles inhibit Streptococcus mutans growth and formation of biofilm

PubMed Central

Hernandez-Delgadillo, Rene; Velasco-Arias, Donaji; Diaz, David; Arevalo-Niño, Katiushka; Garza-Enriquez, Marianela; De la Garza-Ramos, Myriam A; Cabral-Romero, Claudio

2012-01-01

Background and methods Despite continuous efforts, the increasing prevalence of resistance among pathogenic bacteria to common antibiotics has become one of the most significant concerns in modern medicine. Nanostructured materials are used in many fields, including biological sciences and medicine. While some bismuth derivatives has been used in medicine to treat vomiting, nausea, diarrhea, and stomach pain, the biocidal activity of zerovalent bismuth nanoparticles has not yet been studied. The objective of this investigation was to analyze the antimicrobial activity of bismuth nanoparticles against oral bacteria and their antibiofilm capabilities. Results Our results showed that stable colloidal bismuth nanoparticles had 69% antimicrobial activity against Streptococcus mutans growth and achieved complete inhibition of biofilm formation. These results are similar to those obtained with chlorhexidine, the most commonly used oral antiseptic agent. The minimal inhibitory concentration of bismuth nanoparticles that interfered with S. mutans growth was 0.5 mM. Conclusion These results suggest that zerovalent bismuth nanoparticles could be an interesting antimicrobial agent to be incorporated into an oral antiseptic preparation. PMID:22619547

ApoA-I mimetic administration, but not increased apoA-I-containing HDL, inhibits tumour growth in a mouse model of inherited breast cancer.

PubMed

Cedó, Lídia; García-León, Annabel; Baila-Rueda, Lucía; Santos, David; Grijalva, Victor; Martínez-Cignoni, Melanie Raquel; Carbó, José M; Metso, Jari; López-Vilaró, Laura; Zorzano, Antonio; Valledor, Annabel F; Cenarro, Ana; Jauhiainen, Matti; Lerma, Enrique; Fogelman, Alan M; Reddy, Srinivasa T; Escolà-Gil, Joan Carles; Blanco-Vaca, Francisco

2016-11-03

Low levels of high-density lipoprotein cholesterol (HDLc) have been associated with breast cancer risk, but several epidemiologic studies have reported contradictory results with regard to the relationship between apolipoprotein (apo) A-I and breast cancer. We aimed to determine the effects of human apoA-I overexpression and administration of specific apoA-I mimetic peptide (D-4F) on tumour progression by using mammary tumour virus-polyoma middle T-antigen transgenic (PyMT) mice as a model of inherited breast cancer. Expression of human apoA-I in the mice did not affect tumour onset and growth in PyMT transgenic mice, despite an increase in the HDLc level. In contrast, D-4F treatment significantly increased tumour latency and inhibited the development of tumours. The effects of D-4F on tumour development were independent of 27-hydroxycholesterol. However, D-4F treatment reduced the plasma oxidized low-density lipoprotein (oxLDL) levels in mice and prevented oxLDL-mediated proliferative response in human breast adenocarcinoma MCF-7 cells. In conclusion, our study shows that D-4F, but not apoA-I-containing HDL, hinders tumour growth in mice with inherited breast cancer in association with a higher protection against LDL oxidative modification.

ApoA-I mimetic administration, but not increased apoA-I-containing HDL, inhibits tumour growth in a mouse model of inherited breast cancer

PubMed Central

Cedó, Lídia; García-León, Annabel; Baila-Rueda, Lucía; Santos, David; Grijalva, Victor; Martínez-Cignoni, Melanie Raquel; Carbó, José M.; Metso, Jari; López-Vilaró, Laura; Zorzano, Antonio; Valledor, Annabel F.; Cenarro, Ana; Jauhiainen, Matti; Lerma, Enrique; Fogelman, Alan M.; Reddy, Srinivasa T.; Escolà-Gil, Joan Carles; Blanco-Vaca, Francisco

2016-01-01

Low levels of high-density lipoprotein cholesterol (HDLc) have been associated with breast cancer risk, but several epidemiologic studies have reported contradictory results with regard to the relationship between apolipoprotein (apo) A-I and breast cancer. We aimed to determine the effects of human apoA-I overexpression and administration of specific apoA-I mimetic peptide (D-4F) on tumour progression by using mammary tumour virus-polyoma middle T-antigen transgenic (PyMT) mice as a model of inherited breast cancer. Expression of human apoA-I in the mice did not affect tumour onset and growth in PyMT transgenic mice, despite an increase in the HDLc level. In contrast, D-4F treatment significantly increased tumour latency and inhibited the development of tumours. The effects of D-4F on tumour development were independent of 27-hydroxycholesterol. However, D-4F treatment reduced the plasma oxidized low-density lipoprotein (oxLDL) levels in mice and prevented oxLDL-mediated proliferative response in human breast adenocarcinoma MCF-7 cells. In conclusion, our study shows that D-4F, but not apoA-I-containing HDL, hinders tumour growth in mice with inherited breast cancer in association with a higher protection against LDL oxidative modification. PMID:27808249

Curcumin modifies Apc(min) apoptosis resistance and inhibits 2-amino 1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced tumour formation in Apc(min) mice.

PubMed

Collett, G P; Robson, C N; Mathers, J C; Campbell, F C

2001-05-01

Curcumin, the active ingredient of the rhizome of Curcuma longa, promotes apoptosis and may have chemopreventive properties. This study investigates the effects of curcumin on apoptosis and tumorigenesis in male Apc(min) mice treated with the human dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Intestinal epithelial apoptotic index in response to PhIP treatment was approximately twice as great in the wild-type C57BL/6 APC(+/+) strain than in Apc(min) mice (3.7% Apc(+/+) versus 1.9% Apc(min); P < 0.001). PhIP promoted tumour formation in Apc(min) proximal small intestine (4.6 tumours per mouse, PhIP treated versus 2.1 tumours per mouse, control untreated; P < 0.05). Curcumin enhanced PhIP-induced apoptosis (4.0% curcumin + PhIP versus 2.1% PhIP alone; P < 0.01) and inhibited PhIP-induced tumorigenesis in the proximal small intestine of Apc(min) mice (2.2 tumours per mouse, curcumin + PhIP versus 4.6 tumours per mouse PhIP alone; P < 0.05). This study shows that the Apc(min) genotype is associated with resistance to PhIP-induced apoptosis in intestinal epithelium. Curcumin attenuates Apc(min) resistance to PhIP-induced apoptosis and inhibits PhIP-induced tumorigenesis in proximal Apc(min) mouse small intestine.

Radiotherapy Improvements by Using Au Nanoparticles.

PubMed

Torrisi, Lorenzo

2015-01-01

Au nanoparticles can be prepared inside biological solutions and incorporated in special molecules for their transport through blood, drugs and proteins up to the tumour sites or directly injected in their volume when it is possible. The Au nanoparticles are biocompatible and can be accepted locally in the organism also at relatively high concentrations. The use of Au nanoparticles injected in the tumour site enhances significantly the effective atomic number of the medium, depending on the used concentration, and consequently the proton and electron energy loss and the X-ray absorption coefficient determining an increment of the local absorbed dose during radiotherapy. Traditional radiotherapy using electrons, X-rays and gamma rays, and innovative protontherapy can benefit the increment of the effective atomic number of the tissue in the presence of Au-nanoparticles embedded in the tumour volume with an adaptive up-take procedure. This method decreases the dose released to the healthy tissues permitting a better cantering of the irradiated targets and shielding the healthy tissue placed behind the tumour. The presented theoretical study approach permits to evaluate an enhancement of the radiotherapy dose of the order of 1 % using 60 MeV protons, of the order of 10% using 6 MeV electrons and of the order of 100 % using 100 keV X-ray photons. Here, we also disccused for patents relaed to the topic.

Inhibition of Candida albicans biofilm by pure selenium nanoparticles synthesized by pulsed laser ablation in liquids.

PubMed

Guisbiers, Grégory; Lara, Humberto H; Mendoza-Cruz, Ruben; Naranjo, Guillermo; Vincent, Brandy A; Peralta, Xomalin G; Nash, Kelly L

2017-04-01

Selenoproteins play an important role in the human body by accomplishing essential biological functions like oxido-reductions, antioxidant defense, thyroid hormone metabolism and immune response; therefore, the possibility to synthesize selenium nanoparticles free of any contaminants is exciting for future nano-medical applications. This paper reports the first synthesis of selenium nanoparticles by femtosecond pulsed laser ablation in de-ionized water. Those pure nanoparticles have been successfully used to inhibit the formation of Candida albicans biofilms. Advanced electron microscopy images showed that selenium nanoparticles easily adhere on the biofilm, then penetrate into the pathogen, and consequently damage the cell structure by substituting with sulfur. 50% inhibition of Candida albicans biofilm was obtained at only 25 ppm. Finally, the two physical parameters proved to affect strongly the viability of Candida albicans are the crystallinity and particle size. Copyright © 2016 Elsevier Inc. All rights reserved.

Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4

PubMed Central

Harjes, U; Bridges, E; Gharpure, K M; Roxanis, I; Sheldon, H; Miranda, F; Mangala, L S; Pradeep, S; Lopez-Berestein, G; Ahmed, A; Fielding, B; Sood, A K; Harris, A L

2017-01-01

Fatty acid binding protein 4 (FABP4) is a fatty acid chaperone, which is induced during adipocyte differentiation. Previously we have shown that FABP4 in endothelial cells is induced by the NOTCH1 signalling pathway, the latter of which is involved in mechanisms of resistance to antiangiogenic tumour therapy. Here, we investigated the role of FABP4 in endothelial fatty acid metabolism and tumour angiogenesis. We analysed the effect of transient FABP4 knockdown in human umbilical vein endothelial cells on fatty acid metabolism, viability and angiogenesis. Through therapeutic delivery of siRNA targeting mouse FABP4, we investigated the effect of endothelial FABP4 knockdown on tumour growth and blood vessel formation. In vitro, siRNA-mediated FABP4 knockdown in endothelial cells led to a marked increase of endothelial fatty acid oxidation, an increase of reactive oxygen species and decreased angiogenesis. In vivo, we found that increased NOTCH1 signalling in tumour xenografts led to increased expression of endothelial FABP4 that decreased when NOTCH1 and VEGFA inhibitors were used in combination. Angiogenesis, growth and metastasis in ovarian tumour xenografts were markedly inhibited by therapeutic siRNA delivery targeting mouse endothelial FABP4. Therapeutic targeting of endothelial FABP4 by siRNA in vivo has antiangiogenic and antitumour effects with minimal toxicity and should be investigated further. PMID:27568980

Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4.

PubMed

Harjes, U; Bridges, E; Gharpure, K M; Roxanis, I; Sheldon, H; Miranda, F; Mangala, L S; Pradeep, S; Lopez-Berestein, G; Ahmed, A; Fielding, B; Sood, A K; Harris, A L

2017-02-16

Fatty acid binding protein 4 (FABP4) is a fatty acid chaperone, which is induced during adipocyte differentiation. Previously we have shown that FABP4 in endothelial cells is induced by the NOTCH1 signalling pathway, the latter of which is involved in mechanisms of resistance to antiangiogenic tumour therapy. Here, we investigated the role of FABP4 in endothelial fatty acid metabolism and tumour angiogenesis. We analysed the effect of transient FABP4 knockdown in human umbilical vein endothelial cells on fatty acid metabolism, viability and angiogenesis. Through therapeutic delivery of siRNA targeting mouse FABP4, we investigated the effect of endothelial FABP4 knockdown on tumour growth and blood vessel formation. In vitro, siRNA-mediated FABP4 knockdown in endothelial cells led to a marked increase of endothelial fatty acid oxidation, an increase of reactive oxygen species and decreased angiogenesis. In vivo, we found that increased NOTCH1 signalling in tumour xenografts led to increased expression of endothelial FABP4 that decreased when NOTCH1 and VEGFA inhibitors were used in combination. Angiogenesis, growth and metastasis in ovarian tumour xenografts were markedly inhibited by therapeutic siRNA delivery targeting mouse endothelial FABP4. Therapeutic targeting of endothelial FABP4 by siRNA in vivo has antiangiogenic and antitumour effects with minimal toxicity and should be investigated further.

Erythrocyte membrane skeleton inhibits nanoparticle endocytosis

NASA Astrophysics Data System (ADS)

Gao, Xinli; Yue, Tongtao; Tian, Falin; Liu, Zhiping; Zhang, Xianren

2017-06-01

Red blood cells (RBCs), also called erythrocytes, have been experimentally proposed in recent decades as the biological drug delivery systems through entrapping certain drugs by endocytosis. However, the internalization pathway of endocytosis seems to conflict with the robust mechanical properties of RBCs that is induced by the spectrin-actin network of erythrocyte membrane skeleton. In this work, we employed a minimum realistic model and the dissipative particle dynamics method to investigate the influence of the spectrin-actin membrane skeleton on the internalization of nanoparticles (NPs). Our simulations show that the existence of skeleton meshwork indeed induces an inhibiting effect that effectively prevents NPs from internalization. The inhibiting effect is found to depend on the membrane-NP attraction, skeleton tension and relative size of the NP to the membrane skeleton mesh. However, our simulations also demonstrate that there are two possibilities for successful internalization of NPs in the presence of the membrane skeleton. The first case is for NPs that has a much smaller size than the dimension of skeleton meshes, and the other is that the skeleton tension is rather weak so that the formed vesicle can still move inward for NP internalization.

Citrate-Coated Silver Nanoparticles Growth-Independently Inhibit Aflatoxin Synthesis in Aspergillus parasiticus.

PubMed

Mitra, Chandrani; Gummadidala, Phani M; Afshinnia, Kamelia; Merrifield, Ruth C; Baalousha, Mohammed; Lead, Jamie R; Chanda, Anindya

2017-07-18

Manufactured silver nanoparticles (Ag NPs) have long been used as antimicrobials. However, little is known about how these NPs affect fungal cell functions. While multiple previous studies reveal that Ag NPs inhibit secondary metabolite syntheses in several mycotoxin producing filamentous fungi, these effects are associated with growth repression and hence need sublethal to lethal NP doses, which besides stopping fungal growth, can potentially accumulate in the environment. Here we demonstrate that citrate-coated Ag NPs of size 20 nm, when applied at a selected nonlethal dose, can result in a >2 fold inhibition of biosynthesis of the carcinogenic mycotoxin and secondary metabolite, aflatoxin B 1 in the filamentous fungus and an important plant pathogen, Aspergillus parasiticus, without inhibiting fungal growth. We also show that the observed inhibition was not due to Ag ions, but was specifically associated with the mycelial uptake of Ag NPs. The NP exposure resulted in a significant decrease in transcript levels of five aflatoxin genes and at least two key global regulators of secondary metabolism, laeA and veA, with a concomitant reduction of total reactive oxygen species (ROS). Finally, the depletion of Ag NPs in the growth medium allowed the fungus to regain completely its ability of aflatoxin biosynthesis. Our results therefore demonstrate the feasibility of Ag NPs to inhibit fungal secondary metabolism at nonlethal concentrations, hence providing a novel starting point for discovery of custom designed engineered nanoparticles that can efficiently prevent mycotoxins with minimal risk to health and environment.

Anti-tumour therapeutic efficacy of OX40L in murine tumour model.

PubMed

Ali, Selman A; Ahmad, Murrium; Lynam, June; McLean, Cornelia S; Entwisle, Claire; Loudon, Peter; Choolun, Esther; McArdle, Stephanie E B; Li, Geng; Mian, Shahid; Rees, Robert C

2004-09-09

OX40 ligand (OX40L), a member of TNF superfamily, is a co-stimulatory molecule involved in T cell activation. Systemic administration of mOX40L fusion protein significantly inhibited the growth of experimental lung metastasis and subcutaneous (s.c.) established colon (CT26) and breast (4T1) carcinomas. Vaccination with OX40L was significantly enhanced by combination treatment with intra-tumour injection of a disabled infectious single cycle-herpes simplex virus (DISC-HSV) vector encoding murine granulocyte macrophage-colony stimulating factor (mGM-CSF). Tumour rejection in response to OX40L therapy required functional CD4+ and CD8+ T cells and correlated with splenocyte cytotoxic T lymphocytes (CTLs) activity against the AH-1 gp70 peptide of the tumour associated antigen expressed by CT26 cells. These results demonstrate the potential role of the OX40L in cancer immunotherapy.

Magnetic catechin-dextran conjugate as targeted therapeutic for pancreatic tumour cells.

PubMed

Vittorio, Orazio; Voliani, Valerio; Faraci, Paolo; Karmakar, Biswajit; Iemma, Francesca; Hampel, Silke; Kavallaris, Maria; Cirillo, Giuseppe

2014-06-01

Catechin-dextran conjugates have recently attracted a lot of attention due to their anticancer activity against a range of cancer cells. Magnetic nanoparticles have the ability to concentrate therapeutically important drugs due to their magnetic-spatial control and provide opportunities for targeted drug delivery. Enhancement of the anticancer efficiency of catechin-dextran conjugate by functionalisation with magnetic iron oxide nanoparticles. Modification of the coating shell of commercial magnetic nanoparticles (Endorem) composed of dextran with the catechin-dextran conjugate. Catechin-dextran conjugated with Endorem (Endo-Cat) increased the intracellular concentration of the drug and it induced apoptosis in 98% of pancreatic tumour cells placed under magnetic field. The conjugation of catechin-dextran with Endorem enhances the anticancer activity of this drug and provides a new strategy for targeted drug delivery on tumour cells driven by magnetic field. The ability to spatially control the delivery of the catechin-dextran by magnetic field makes it a promising agent for further application in cancer therapy.

A review on hyperthermia via nanoparticle-mediated therapy.

PubMed

Sohail, Ayesha; Ahmad, Zaki; Bég, O Anwar; Arshad, Sarmad; Sherin, Lubna

2017-05-01

Hyperthermia treatment, generated by magnetic nanoparticles (MNPs) is promising since it is tumour-focused, minimally invasive and uniform. The most unique feature of magnetic nanoparticles is its reaction and modulation by a magnetic force basically responsible for enabling its potential as heating mediators for cancer therapy. In magnetic nanoparticle hyperthermia, a tumour is preferentially loaded with systemically administered nanoparticles with high-absorption cross-section for transduction of an extrinsic energy source to heat. To maximize the energy deposited in the tumour while limiting the exposure to healthy tissues, the heating is achieved by exposing the region of tissue containing magnetic nanoparticles to an alternating magnetic field. The magnetic nanoparticles dissipate heat from relaxation losses thereby heating localized tissue above normal physiological ranges. Besides thermal efficiency, the biocompatibility of magnetite nanoparticles assisted its deployment as efficient drug carrier for targeted therapeutic regimes. In the present article, we provide a state-of-the-art review focused on progress in nanoparticle induced hyperthermia treatments that have several potential advantages over both global and local hyperthermia treatments achieved without nanoparticles. Green bio-nanotechnology has attracted substantial attention and has demonstrable abilities to improve cancer therapy. Furthermore, we have listed the challenges associated with this treatment along with future prospective that could attract the interest of biomedical engineers, biomaterials scientists, medical researchers and pharmacological research groups. Copyright © 2017 Société Française du Cancer. All rights reserved.

Pulsation-limited oxygen diffusion in the tumour microenvironment

NASA Astrophysics Data System (ADS)

Milotti, Edoardo; Stella, Sabrina; Chignola, Roberto

2017-01-01

Hypoxia is central to tumour evolution, growth, invasion and metastasis. Mathematical models of hypoxia based on reaction-diffusion equations provide seemingly incomplete descriptions as they fail to predict the measured oxygen concentrations in the tumour microenvironment. In an attempt to explain the discrepancies, we consider both the inhomogeneous distribution of oxygen-consuming cells in solid tumours and the dynamics of blood flow in the tumour microcirculation. We find that the low-frequency oscillations play an important role in the establishment of tumour hypoxia. The oscillations interact with consumption to inhibit oxygen diffusion in the microenvironment. This suggests that alpha-blockers-a class of drugs used to treat hypertension and stress disorders, and known to lower or even abolish low-frequency oscillations of arterial blood flow -may act as adjuvant drugs in the radiotherapy of solid tumours by enhancing the oxygen effect.

Cyclooxygenase inhibitors are potent sensitizers of prostate tumours to hyperthermia and radiation.

PubMed

Asea, A; Mallick, R; Lechpammer, S; Ara, G; Teicher, B A; Fiorentino, S; Stevenson, M A; Calderwood, S K

2001-01-01

It has previously been demonstrated that hyperthermia can activate prostaglandin synthesis and that prostaglandins are protective against hyperthermia. This study examined the use of inhibitors of prostaglandin synthesis on the response of prostate tumours to hyperthermia. The non-steroidal anti-inflammatory drugs (NSAID) ibuprofen and sulindac, known cyclooxygenase inhibitors that inhibit prostaglandin production, were effective hyperthermia sensitizers and augmented growth delay of DU-145 and PC-3 prostate tumours to combined radiation and hyperthermia treatment protocols. Pre-treatment of mice with ibuprofen and sulindac at hyperthermia sensitizing doses resulted in significant (p < 0.01) inhibition of hyperthemia-induced serum prostaglandin E2. These findings indicate that NSAID may have both sensitizing effects on prostate tumour growth and may function by inhibiting prostaglandin synthesis.

A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

NASA Astrophysics Data System (ADS)

Duivenvoorden, Raphaël; Tang, Jun; Cormode, David P.; Mieszawska, Aneta J.; Izquierdo-Garcia, David; Ozcan, Canturk; Otten, Maarten J.; Zaidi, Neeha; Lobatto, Mark E.; van Rijs, Sarian M.; Priem, Bram; Kuan, Emma L.; Martel, Catherine; Hewing, Bernd; Sager, Hendrik; Nahrendorf, Matthias; Randolph, Gwendalyn J.; Stroes, Erik S. G.; Fuster, Valentin; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J. M.

2014-01-01

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

Alpha-alumina nanoparticles induce efficient autophagy-dependent cross-presentation and potent antitumour response

NASA Astrophysics Data System (ADS)

Li, Haiyan; Li, Yuhuan; Jiao, Jun; Hu, Hong-Ming

2011-10-01

Therapeutic cancer vaccination is an attractive strategy because it induces T cells of the immune system to recognize and kill tumour cells in cancer patients. However, it remains difficult to generate large numbers of T cells that can recognize the antigens on cancer cells using conventional vaccine carrier systems. Here we show that α-Al2O3 nanoparticles can act as an antigen carrier to reduce the amount of antigen required to activate T cells in vitro and in vivo. We found that α-Al2O3 nanoparticles delivered antigens to autophagosomes in dendritic cells, which then presented the antigens to T cells through autophagy. Immunization of mice with α-Al2O3 nanoparticles that are conjugated to either a model tumour antigen or autophagosomes derived from tumour cells resulted in tumour regression. These results suggest that α-Al2O3 nanoparticles may be a promising adjuvant in the development of therapeutic cancer vaccines.

A paclitaxel-loaded recombinant polypeptide nanoparticle outperforms Abraxane in multiple murine cancer models

NASA Astrophysics Data System (ADS)

Bhattacharyya, Jayanta; Bellucci, Joseph J.; Weitzhandler, Isaac; McDaniel, Jonathan R.; Spasojevic, Ivan; Li, Xinghai; Lin, Chao-Chieh; Chi, Jen-Tsan Ashley; Chilkoti, Ashutosh

2015-08-01

Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumour-specific uptake and therapeutic potential. To this end, here we conjugated paclitaxel (PTX) to recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into ~60 nm near-monodisperse nanoparticles that increased the systemic exposure of PTX by sevenfold compared with free drug and twofold compared with the Food and Drug Administration-approved taxane nanoformulation (Abraxane). The tumour uptake of the CP-PTX nanoparticle was fivefold greater than free drug and twofold greater than Abraxane. In a murine cancer model of human triple-negative breast cancer and prostate cancer, CP-PTX induced near-complete tumour regression after a single dose in both tumour models, whereas at the same dose, no mice treated with Abraxane survived for >80 days (breast) and 60 days (prostate), respectively. These results show that a molecularly engineered nanoparticle with precisely engineered design features outperforms Abraxane, the current gold standard for PTX delivery.

Delivery of chemotherapeutic drugs in tumour cell-derived microparticles.

PubMed

Tang, Ke; Zhang, Yi; Zhang, Huafeng; Xu, Pingwei; Liu, Jing; Ma, Jingwei; Lv, Meng; Li, Dapeng; Katirai, Foad; Shen, Guan-Xin; Zhang, Guimei; Feng, Zuo-Hua; Ye, Duyun; Huang, Bo

2012-01-01

Cellular microparticles are vesicular plasma membrane fragments with a diameter of 100-1,000 nanometres that are shed by cells in response to various physiological and artificial stimuli. Here we demonstrate that tumour cell-derived microparticles can be used as vectors to deliver chemotherapeutic drugs. We show that tumour cells incubated with chemotherapeutic drugs package these drugs into microparticles, which can be collected and used to effectively kill tumour cells in murine tumour models without typical side effects. We describe several mechanisms involved in this process, including uptake of drug-containing microparticles by tumour cells, synthesis of additional drug-packaging microparticles by these cells that contribute to the cytotoxic effect and the inhibition of drug efflux from tumour cells. This study highlights a novel drug delivery strategy with potential clinical application.

In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer

NASA Astrophysics Data System (ADS)

Lizotte, P. H.; Wen, A. M.; Sheen, M. R.; Fields, J.; Rojanasopondist, P.; Steinmetz, N. F.; Fiering, S.

2016-03-01

Nanotechnology has tremendous potential to contribute to cancer immunotherapy. The ‘in situ vaccination’ immunotherapy strategy directly manipulates identified tumours to overcome local tumour-mediated immunosuppression and subsequently stimulates systemic antitumour immunity to treat metastases. We show that inhalation of self-assembling virus-like nanoparticles from cowpea mosaic virus (CPMV) reduces established B16F10 lung melanoma and simultaneously generates potent systemic antitumour immunity against poorly immunogenic B16F10 in the skin. Full efficacy required Il-12, Ifn-γ, adaptive immunity and neutrophils. Inhaled CPMV nanoparticles were rapidly taken up by and activated neutrophils in the tumour microenvironment as an important part of the antitumour immune response. CPMV also exhibited clear treatment efficacy and systemic antitumour immunity in ovarian, colon, and breast tumour models in multiple anatomic locations. CPMV nanoparticles are stable, nontoxic, modifiable with drugs and antigens, and their nanomanufacture is highly scalable. These properties, combined with their inherent immunogenicity and demonstrated efficacy against a poorly immunogenic tumour, make CPMV an attractive and novel immunotherapy against metastatic cancer.

ZnO nanoparticles inhibit Pseudomonas aeruginosa biofilm formation and virulence factor production.

PubMed

Lee, Jin-Hyung; Kim, Yong-Guy; Cho, Moo Hwan; Lee, Jintae

2014-12-01

The opportunistic pathogen Pseudomonas aeruginosa produces a variety of virulence factors, and biofilms of this bacterium are much more resistant to antibiotics than planktonic cells. Thirty-six metal ions have been investigated to identify antivirulence and antibiofilm metal ions. Zinc ions and ZnO nanoparticles were found to markedly inhibit biofilm formation and the production of pyocyanin, Pseudomonas quinolone signal (PQS), pyochelin, and hemolytic activity of P. aeruginosa without affecting the growth of planktonic cells. Transcriptome analyses showed that ZnO nanoparticles induce the zinc cation efflux pump czc operon and several important transcriptional regulators (porin gene opdT and type III repressor ptrA), but repress the pyocyanin-related phz operon, which explains observed phenotypic changes. A mutant study showed that the effects of ZnO nanoparticles on the control of pyocyanin production and biofilm formation require the czc regulator CzcR. In addition, ZnO nanoparticles markedly increased the cellular hydrophilicity of P. aeruginosa cells. Our results support that ZnO nanoparticles are potential antivirulence materials against recalcitrant P. aeruginosa infections and possibly other important pathogens. Copyright © 2014 Elsevier GmbH. All rights reserved.

Enzyme and Cancer Cell Selectivity of Nanoparticles: Inhibition of 3D Metastatic Phenotype and Experimental Melanoma by Zinc Oxide.

PubMed

DeLong, Robert K; Mitchell, Jennifer A; Morris, R Tyler; Comer, Jeffrey; Hurst, Miranda N; Ghosh, Kartik; Wanekaya, Adam; Mudge, Miranda; Schaeffer, Ashley; Washington, Laurie L; Risor-Marhanka, Azure; Thomas, Spencer; Marroquin, Shanna; Lekey, Amber; Smith, Joshua J; Garrad, Richard; Aryal, Santosh; Abdelhakiem, Mohamed; Glaspell, Garry P

2017-02-01

Biomedical applications for metal and metal oxide nanoparticles are rapidly increasing. Here their functional impact on two well-characterized model enzymes, Luciferase (Luc) or β-galactosidase (β-Gal) was quantitatively compared. Nickel oxide nanoparticle (NiO-NP) activated β-Gal (>400% control) and boron carbide nanoparticle (B4C-NP) inhibited Luc(<10% control), whereas zinc oxide (ZnO-NP) and cobalt oxide (Co3O4-NP) activated β-Gal to a lesser extent and magnesium oxide (MgO) moderately inhibited both enzymes. Melanoma specific killing was in the order; ZnO > B4C ≥ Cu > MgO > Co3O4 > Fe2O3 > NiO, ZnO-NP inhibiting B16F10 and A375 cells as well as ERK enzyme (>90%) and several other cancer-associated kinases (AKT, CREB, p70S6K). ZnO-NP or nanobelt (NB) serve as photoluminescence (PL) cell labels and inhibit 3-D multi-cellular tumor spheroid (MCTS) growth and were tested in a mouse melanoma model. These results demonstrate nanoparticle and enzyme specific biochemical activity and suggest their utility as new tools to explore the important model metastatic foci 3-D environment and their chemotherapeutic potential.

Inhibition of E. coli and S. aureus with selenium nanoparticles synthesized by pulsed laser ablation in deionized water

PubMed Central

Guisbiers, G; Wang, Q; Khachatryan, E; Mimun, LC; Mendoza-Cruz, R; Larese-Casanova, P; Webster, TJ; Nash, KL

2016-01-01

Nosocomial diseases are mainly caused by two common pathogens, Escherichia coli and Staphylococcus aureus, which are becoming more and more resistant to conventional antibiotics. Therefore, it is becoming increasingly necessary to find other alternative treatments than commonly utilized drugs. A promising strategy is to use nanomaterials such as selenium nanoparticles. However, the ability to produce nanoparticles free of any contamination is very challenging, especially for nano-medical applications. This paper reports the successful synthesis of pure selenium nanoparticles by laser ablation in water and determines the minimal concentration required for ~50% inhibition of either E. coli or S. aureus after 24 hours to be at least ~50 ppm. Total inhibition of E. coli and S. aureus is expected to occur at 107±12 and 79±4 ppm, respectively. In this manner, this study reports for the first time an easy synthesis process for creating pure selenium to inhibit bacterial growth. PMID:27563240

Inhibition of E. coli and S. aureus with selenium nanoparticles synthesized by pulsed laser ablation in deionized water.

PubMed

Guisbiers, G; Wang, Q; Khachatryan, E; Mimun, L C; Mendoza-Cruz, R; Larese-Casanova, P; Webster, T J; Nash, K L

2016-01-01

Nosocomial diseases are mainly caused by two common pathogens, Escherichia coli and Staphylococcus aureus, which are becoming more and more resistant to conventional antibiotics. Therefore, it is becoming increasingly necessary to find other alternative treatments than commonly utilized drugs. A promising strategy is to use nanomaterials such as selenium nanoparticles. However, the ability to produce nanoparticles free of any contamination is very challenging, especially for nano-medical applications. This paper reports the successful synthesis of pure selenium nanoparticles by laser ablation in water and determines the minimal concentration required for ~50% inhibition of either E. coli or S. aureus after 24 hours to be at least ~50 ppm. Total inhibition of E. coli and S. aureus is expected to occur at 107±12 and 79±4 ppm, respectively. In this manner, this study reports for the first time an easy synthesis process for creating pure selenium to inhibit bacterial growth.

Maximizing tumour exposure to anti-neuropilin-1 antibody requires saturation of non-tumour tissue antigenic sinks in mice

PubMed Central

Bumbaca, Daniela; Xiang, Hong; Boswell, C Andrew; Port, Ruediger E; Stainton, Shannon L; Mundo, Eduardo E; Ulufatu, Sheila; Bagri, Anil; Theil, Frank-Peter; Fielder, Paul J; Khawli, Leslie A; Shen, Ben-Quan

2012-01-01

BACKGROUND AND PURPOSE Neuropilin-1 (NRP1) is a VEGF receptor that is widely expressed in normal tissues and is involved in tumour angiogenesis. MNRP1685A is a rodent and primate cross-binding human monoclonal antibody against NRP1 that exhibits inhibition of tumour growth in NPR1-expressing preclinical models. However, widespread NRP1 expression in normal tissues may affect MNRP1685A tumour uptake. The objective of this study was to assess MNRP1685A biodistribution in tumour-bearing mice to understand the relationships between dose, non-tumour tissue uptake and tumour uptake. EXPERIMENTAL APPROACH Non-tumour-bearing mice were given unlabelled MNRP1685A at 10 mg·kg−1. Tumour-bearing mice were given 111In-labelled MNRP1685A along with increasing amounts of unlabelled antibody. Blood and tissues were collected from all animals to determine drug concentration (unlabelled) or radioactivity level (radiolabelled). Some animals were imaged using single photon emission computed tomography – X-ray computed tomography. KEY RESULTS MNRP1685A displayed faster serum clearance than pertuzumab, indicating that target binding affected MNRP1685A clearance. I.v. administration of 111In-labelled MNRP1685A to tumour-bearing mice yielded minimal radioactivity in the plasma and tumour, but high levels in the lungs and liver. Co-administration of unlabelled MNRP1685A with the radiolabelled antibody was able to competitively block lungs and liver radioactivity uptake in a dose-dependent manner while augmenting plasma and tumour radioactivity levels. CONCLUSIONS AND IMPLICATIONS These results indicate that saturation of non-tumour tissue uptake is required in order to achieve tumour uptake and acceptable exposure to antibody. Utilization of a rodent and primate cross-binding antibody allows for translation of these results to clinical settings. PMID:22074316

Maximizing tumour exposure to anti-neuropilin-1 antibody requires saturation of non-tumour tissue antigenic sinks in mice.

PubMed

Bumbaca, Daniela; Xiang, Hong; Boswell, C Andrew; Port, Ruediger E; Stainton, Shannon L; Mundo, Eduardo E; Ulufatu, Sheila; Bagri, Anil; Theil, Frank-Peter; Fielder, Paul J; Khawli, Leslie A; Shen, Ben-Quan

2012-05-01

Neuropilin-1 (NRP1) is a VEGF receptor that is widely expressed in normal tissues and is involved in tumour angiogenesis. MNRP1685A is a rodent and primate cross-binding human monoclonal antibody against NRP1 that exhibits inhibition of tumour growth in NPR1-expressing preclinical models. However, widespread NRP1 expression in normal tissues may affect MNRP1685A tumour uptake. The objective of this study was to assess MNRP1685A biodistribution in tumour-bearing mice to understand the relationships between dose, non-tumour tissue uptake and tumour uptake. Non-tumour-bearing mice were given unlabelled MNRP1685A at 10 mg·kg(-1) . Tumour-bearing mice were given (111) In-labelled MNRP1685A along with increasing amounts of unlabelled antibody. Blood and tissues were collected from all animals to determine drug concentration (unlabelled) or radioactivity level (radiolabelled). Some animals were imaged using single photon emission computed tomography - X-ray computed tomography. MNRP1685A displayed faster serum clearance than pertuzumab, indicating that target binding affected MNRP1685A clearance. I.v. administration of (111) In-labelled MNRP1685A to tumour-bearing mice yielded minimal radioactivity in the plasma and tumour, but high levels in the lungs and liver. Co-administration of unlabelled MNRP1685A with the radiolabelled antibody was able to competitively block lungs and liver radioactivity uptake in a dose-dependent manner while augmenting plasma and tumour radioactivity levels. These results indicate that saturation of non-tumour tissue uptake is required in order to achieve tumour uptake and acceptable exposure to antibody. Utilization of a rodent and primate cross-binding antibody allows for translation of these results to clinical settings. © 2011 Genentech Inc. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Further Observations on the Effect of C. parvum and Anti-Tumour Globulin on Syngeneically Transplanted Mouse Tumours

PubMed Central

Woodruff, M. F. A.; Inchley, M. P.; Dunbar, Noreen

1972-01-01

The inhibitory effect of an i.v. or i.p. injection of C. parvum on intrastrain transplants of a mammary carcinoma in A/HeJ mice has been confirmed, and it has been shown further that C. parvum inhibits the growth of transplants of sarcomata induced with methylcholanthrene both in this strain (members of which lack the fifth component of complement) and in CBA mice (which are not complement deficient). In experiments with the mammary carcinoma, 2 injections of C. parvum on days + 3 and + 9 were more effective than a single injection on day + 3; injections on days + 3 and + 6, or + 3 and + 12, appeared to be marginally less effective than on days + 3 and + 9, but the difference was not statistically significant. Development of the CBA sarcoma was inhibited to about the same extent if, instead of treating the mouse with C. parvum, the tumour cells were pre-incubated with anti-tumour globulin (ATG) in the absence of complement prior to inoculation, and the effect of combining these procedures was much greater than that of either alone. Pre-incubation with ATG had a similar but less marked effect on the development of the mammary carcinoma but had no effect on the A/HeJ sarcoma. Injection (i.v.) of ATG did not inhibit the growth of any of the tumours in these experiments and possible reasons for this are discussed. PMID:5038327

Diagnostic nanoparticle targeting of the EGF-receptor in complex biological conditions using single-domain antibodies.

PubMed

Zarschler, K; Prapainop, K; Mahon, E; Rocks, L; Bramini, M; Kelly, P M; Stephan, H; Dawson, K A

2014-06-07

For effective localization of functionalized nanoparticles at diseased tissues such as solid tumours or metastases through biorecognition, appropriate targeting vectors directed against selected tumour biomarkers are a key prerequisite. The diversity of such vector molecules ranges from proteins, including antibodies and fragments thereof, through aptamers and glycans to short peptides and small molecules. Here, we analyse the specific nanoparticle targeting capabilities of two previously suggested peptides (D4 and GE11) and a small camelid single-domain antibody (sdAb), representing potential recognition agents for the epidermal growth factor receptor (EGFR). We investigate specificity by way of receptor RNA silencing techniques and look at increasing complexity in vitro by introducing increasing concentrations of human or bovine serum. Peptides D4 and GE11 proved problematic to employ and conjugation resulted in non-receptor specific uptake into cells. Our results show that sdAb-functionalized particles can effectively target the EGFR, even in more complex bovine and human serum conditions where targeting specificity is largely conserved for increasing serum concentration. In human serum however, an inhibition of overall nanoparticle uptake is observed with increasing protein concentration. For highly affine targeting ligands such as sdAbs, targeting a receptor such as EGFR with low serum competitor abundance, receptor recognition function can still be partially realised in complex conditions. Here, we stress the value of evaluating the targeting efficiency of nanoparticle constructs in realistic biological milieu, prior to more extensive in vivo studies.

Short-term dietary copper deficiency does not inhibit angiogenesis in tumours implanted in striated muscle.

PubMed Central

Schuschke, D. A.; Reed, M. W.; Saari, J. T.; Olson, M. D.; Ackermann, D. M.; Miller, F. N.

1992-01-01

The effect of dietary copper deficiency on tumour growth, neovascularisation and microvascular integrity was studied in the rat cremaster muscle. Male, weanling Sprague-Dawley rats were fed purified diets which were copper deficient (< 0.5 micrograms g-1 of diet) or copper adequate (5 micrograms g-1 of diet). Seven days after initiation of diets, a chondrosarcoma was implanted in the cremaster muscle of each rat. Five, 10 or 20 days after tumour implantation, rats were anesthetised and their cremasters prepared for observation by intravital microscopy. Intraarterial injection of fluorescein isothiocyanate-conjugated albumin and subsequent observation of fluorescence in the perivascular space indicated no difference in microvascular albumin leakage between the tumour vasculature of copper deficient and copper adequate rats. Neither tumour growth (assessed by wet weight), vascular density (assessed by light microscopy), nor any ultrastructural characteristics of the tumour or its vasculature (assessed by electron microscopy) were affected by copper deficiency. In view of findings by others which indicate changes in tumour characteristics with copper deficiency, we conclude that the copper dependency of tumour growth and vascularisation is a function of the type of tumour, the host tissue, or the conditions of copper depletion. PMID:1280989

The 3p14.2 tumour suppressor ADAMTS9 is inactivated by promoter CpG methylation and inhibits tumour cell growth in breast cancer.

PubMed

Shao, Bianfei; Feng, Yixiao; Zhang, Hongbin; Yu, Fang; Li, Qianqian; Tan, Cui; Xu, Hongying; Ying, Jianming; Li, Lili; Yang, Dejuan; Peng, Weiyan; Tang, Jun; Li, Shuman; Ren, Guosheng; Tao, Qian; Xiang, Tingxiu

2018-02-01

Chromosome region 3p12-14 is an important tumour suppressor gene (TSG) locus for multiple cancers. ADAMTS9, a member of the metalloprotease large family, has been identified as a candidate 3p14.2 TSG inactivated by aberrant promoter CpG methylation in several carcinomas, but little known about its expression and function in breast cancer. In this report, ADAMTS9 expression and methylation was analysed in breast cancer cell lines and tissue samples. ADAMTS9 RNA was significantly down-regulated in breast cancer cell lines (6/8). After treating the cells with demethylation agent Aza and TSA, ADAMTS9 expression was dramatically increased. Bisulphite genomic sequencing and methylation-specific PCR detected promoter methylation, which was associated with decreased ADAMTS9 expression. Hypermethylation was also detected in 130/219 (59.4%) of primary tumours but only in 4.5% (2/44) of paired surgical margin tissues. Ectopic expression of ADAMTS9 in tumor cells induced significant growth suppression, cell cycle arrest at the G0/G1 phase, enhanced apoptosis and reduced cell migration and invasion. Conditioned culture medium from ADAMTS9-transfected BT549 cells markedly disrupted tube formation ability of human umbilical vein endothelial cell (HUVEC) in Matrigel. Furthermore, ADAMTS9 inhibited AKT signaling and its downstream targets (MDM2, p53, p21, p27, E-cadherin, VIM, SNAIL, VEGFA, NFκB-p65 and MMP2). In addition, we demonstrated, for the first time, that ADAMTS9 inhibits AKT signaling, through suppressing its upstream activators EGFR and TGFβ1/TβR(I/II) in breast cancer cells. Our results suggest that ADAMTS9 is a TSG epigenetically inactivated in breast cancer, which functions through blocking EGFR- and TGFβ1/TβR(I/II)-activated AKT signaling. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

α3 Chains of type V collagen regulate breast tumour growth via glypican-1

PubMed Central

Huang, Guorui; Ge, Gaoxiang; Izzi, Valerio; Greenspan, Daniel S.

2017-01-01

Pericellular α3(V) collagen can affect the functioning of cells, such as adipocytes and pancreatic β cells. Here we show that α3(V) chains are an abundant product of normal mammary gland basal cells, and that α3(V) ablation in a mouse mammary tumour model inhibits mammary tumour progression by reducing the proliferative potential of tumour cells. These effects are shown to be primarily cell autonomous, from loss of α3(V) chains normally produced by tumour cells, in which they affect growth by enhancing the ability of cell surface proteoglycan glypican-1 to act as a co-receptor for FGF2. Thus, a mechanism is presented for microenvironmental influence on tumour growth. α3(V) chains are produced in both basal-like and luminal human breast tumours, and its expression levels are tightly coupled with those of glypican-1 across breast cancer types. Evidence indicates α3(V) chains as potential targets for inhibiting tumour growth and as markers of oncogenic transformation. PMID:28102194

Targeted Delivery of Glucan Particle Encapsulated Gallium Nanoparticles Inhibits HIV Growth in Human Macrophages

PubMed Central

Soto, Ernesto R.; O'Connell, Olivia; Dikengil, Fusun; Peters, Paul J.; Clapham, Paul R.

2016-01-01

Glucan particles (GPs) are hollow, porous 3–5 μm microspheres derived from the cell walls of Baker's yeast (Saccharomyces cerevisiae). The 1,3-β-glucan outer shell provides for receptor-mediated uptake by phagocytic cells expressing β-glucan receptors. GPs have been used for macrophage-targeted delivery of a wide range of payloads (DNA, siRNA, protein, small molecules, and nanoparticles) encapsulated inside the hollow GPs or bound to the surface of chemically derivatized GPs. Gallium nanoparticles have been proposed as an inhibitory agent against HIV infection. Here, macrophage targeting of gallium using GPs provides for more efficient delivery of gallium and inhibition of HIV infection in macrophages compared to free gallium nanoparticles. PMID:27965897

Magnesium silicide nanoparticles as a deoxygenation agent for cancer starvation therapy

NASA Astrophysics Data System (ADS)

Zhang, Chen; Ni, Dalong; Liu, Yanyan; Yao, Heliang; Bu, Wenbo; Shi, Jianlin

2017-05-01

A material that rapidly absorbs molecular oxygen (known as an oxygen scavenger or deoxygenation agent (DOA)) has various industrial applications, such as in food preservation, anticorrosion of metal and coal deoxidation. Given that oxygen is vital to cancer growth, to starve tumours through the consumption of intratumoral oxygen is a potentially useful strategy in fighting cancer. Here we show that an injectable polymer-modified magnesium silicide (Mg2Si) nanoparticle can act as a DOA by scavenging oxygen in tumours and form by-products that block tumour capillaries from being reoxygenated. The nanoparticles are prepared by a self-propagating high-temperature synthesis strategy. In the acidic tumour microenvironment, the Mg2Si releases silane, which efficiently reacts with both tissue-dissolved and haemoglobin-bound oxygen to form silicon oxide (SiO2) aggregates. This in situ formation of SiO2 blocks the tumour blood capillaries and prevents tumours from receiving new supplies of oxygen and nutrients.

Magnesium silicide nanoparticles as a deoxygenation agent for cancer starvation therapy.

PubMed

Zhang, Chen; Ni, Dalong; Liu, Yanyan; Yao, Heliang; Bu, Wenbo; Shi, Jianlin

2017-05-01

A material that rapidly absorbs molecular oxygen (known as an oxygen scavenger or deoxygenation agent (DOA)) has various industrial applications, such as in food preservation, anticorrosion of metal and coal deoxidation. Given that oxygen is vital to cancer growth, to starve tumours through the consumption of intratumoral oxygen is a potentially useful strategy in fighting cancer. Here we show that an injectable polymer-modified magnesium silicide (Mg 2 Si) nanoparticle can act as a DOA by scavenging oxygen in tumours and form by-products that block tumour capillaries from being reoxygenated. The nanoparticles are prepared by a self-propagating high-temperature synthesis strategy. In the acidic tumour microenvironment, the Mg 2 Si releases silane, which efficiently reacts with both tissue-dissolved and haemoglobin-bound oxygen to form silicon oxide (SiO 2 ) aggregates. This in situ formation of SiO 2 blocks the tumour blood capillaries and prevents tumours from receiving new supplies of oxygen and nutrients.

Effect of chemically and biologically synthesized Ag nanoparticles on the algae growth inhibition

NASA Astrophysics Data System (ADS)

Anna, Mražiková; Oksana, Velgosová; Jana, Kavuličová

2017-12-01

Over the past few years green methods for preparation of silver nanoparticles has become necessary due to its friendly influence on ecosystem. In the present work antimicrobial properties of biologically synthesized silver nanoparticles (Bio-AgNPs) using green algae extract and chemically synthesized silver nanoparticles (Chem-AgNPs) using sodium citrate against algae Parachlorella kessleri is investigated. Both used Bio-AgNPs and Chem-AgNPs exhibit long-term stability as demonstrated by UV-vis spectroscopy measurements. The results revealed stronger toxic effects of Bio-AgNPs on agar plates what was confirmed clear inhibition zone around wells impregnated with Bio-AgNPs. On the other hand Bio-AgNPs were confirmed to be less toxic in aquatic environments for the growths of green algae P. kessleri comparing to Chem-AgNPs.

Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours.

PubMed

Tate, Sonya C; Burke, Teresa F; Hartman, Daisy; Kulanthaivel, Palaniappan; Beckmann, Richard P; Cronier, Damien M

2016-03-15

Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the quantitative pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation. A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival. The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression. The quantitative pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified.

Evaluation of E. coli inhibition by plain and polymer-coated silver nanoparticles.

PubMed

Ashmore, D'Andrea; Chaudhari, Atul; Barlow, Brandi; Barlow, Brett; Harper, Talia; Vig, Komal; Miller, Michael; Singh, Shree; Nelson, Edward; Pillai, Shreekumar

2018-01-01

Escherichia coli causes various ailments such as septicemia, enteritis, foodborne illnesses, and urinary tract infections which are of concern in the public health field due to antibiotic resistance. Silver nanoparticles (AgNP) are known for their biocompatibility and antibacterial activity, and may prove to be an alternative method of treatment, especially as wound dressings. In this study, we compared the antibacterial efficacy of two polymer-coated silver nanoparticles either containing 10% Ag (Ag 10% + Polymer), or 99% Ag (AgPVP) in relation to plain uncoated silver nanoparticles (AgNP). Atomic force microscopy was used to characterize the nanoparticles, and their antibacterial efficacy was compared by the minimum inhibitory concentration (MIC) and bacterial growth curve assays, followed by molecular studies using scanning electron microscopy (SEM) and (qRT- PCR). AgNP inhibited the growth of E. coli only at 0.621 mg/mL, which was double the concentration required for both coated nanoparticles (0.312 mg/mL). Similarly, bacterial growth was impeded as early as 8 h at 0.156 mg/mL of both coated nanoparticles as compared to 0.312 mg/mL for plain AgNP. SEM data showed that nanoparticles damaged the cell membrane, resulting in bacterial cell lysis, expulsion of cellular contents, and complete disintegration of some cells. The expression of genes associated with the TCA cycle (aceF and frdB) and amino acid metabolism (gadB, metL, argC) were substantially downregulated in E. coli treated with nanoparticles. The reduction in the silver ion (Ag+) concentration of polymer-coated AgNP did not affect their antibacterial efficacy against E. coli.

Optimizing Therapeutic Effect of Aurora B Inhibition in Acute Myeloid Leukemia with AZD2811 Nanoparticles.

PubMed

Floc'h, Nicolas; Ashton, Susan; Taylor, Paula; Trueman, Dawn; Harris, Emily; Odedra, Rajesh; Maratea, Kim; Derbyshire, Nicola; Caddy, Jacqueline; Jacobs, Vivien N; Hattersley, Maureen; Wen, Shenghua; Curtis, Nicola J; Pilling, James E; Pease, Elizabeth J; Barry, Simon T

2017-06-01

Barasertib (AZD1152), a highly potent and selective aurora kinase B inhibitor, gave promising clinical activity in elderly acute myeloid leukemia (AML) patients. However, clinical utility was limited by the requirement for a 7-day infusion. Here we assessed the potential of a nanoparticle formulation of the selective Aurora kinase B inhibitor AZD2811 (formerly known as AZD1152-hQPA) in preclinical models of AML. When administered to HL-60 tumor xenografts at a single dose between 25 and 98.7 mg/kg, AZD2811 nanoparticle treatment delivered profound inhibition of tumor growth, exceeding the activity of AZD1152. The improved antitumor activity was associated with increased phospho-histone H3 inhibition, polyploidy, and tumor cell apoptosis. Moreover, AZD2811 nanoparticles increased antitumor activity when combined with cytosine arabinoside. By modifying dose of AZD2811 nanoparticle, therapeutic benefit in a range of preclinical models was further optimized. At high-dose, antitumor activity was seen in a range of models including the MOLM-13 disseminated model. At these higher doses, a transient reduction in bone marrow cellularity was observed demonstrating the potential for the formulation to target residual disease in the bone marrow, a key consideration when treating AML. Collectively, these data establish that AZD2811 nanoparticles have activity in preclinical models of AML. Targeting Aurora B kinase with AZD2811 nanoparticles is a novel approach to deliver a cell-cycle inhibitor in AML, and have potential to improve on the clinical activity seen with cell-cycle agents in this disease. Mol Cancer Ther; 16(6); 1031-40. ©2017 AACR . ©2017 American Association for Cancer Research.

Curcumin modified silver nanoparticles for highly efficient inhibition of respiratory syncytial virus infection

NASA Astrophysics Data System (ADS)

Yang, Xiao Xi; Li, Chun Mei; Huang, Cheng Zhi

2016-01-01

Interactions between nanoparticles and viruses have attracted increasing attention due to the antiviral activity of nanoparticles and the resulting possibility to be employed as biomedical interventions. In this contribution, we developed a very simple route to prepare uniform and stable silver nanoparticles (AgNPs) with antiviral properties by using curcumin, which is a member of the ginger family isolated from rhizomes of the perennial herb Curcuma longa and has a wide range of biological activities like antioxidant, antifungal, antibacterial and anti-inflammatory effects, and acts as reducing and capping agents in this synthetic route. The tissue culture infectious dose (TCID50) assay showed that the curcumin modified silver nanoparticles (cAgNPs) have a highly efficient inhibition effect against respiratory syncytial virus (RSV) infection, giving a decrease of viral titers about two orders of magnitude at the concentration of cAgNPs under which no toxicity was found to the host cells. Mechanism investigations showed that cAgNPs could prevent RSV from infecting the host cells by inactivating the virus directly, indicating that cAgNPs are a novel promising efficient virucide for RSV.Interactions between nanoparticles and viruses have attracted increasing attention due to the antiviral activity of nanoparticles and the resulting possibility to be employed as biomedical interventions. In this contribution, we developed a very simple route to prepare uniform and stable silver nanoparticles (AgNPs) with antiviral properties by using curcumin, which is a member of the ginger family isolated from rhizomes of the perennial herb Curcuma longa and has a wide range of biological activities like antioxidant, antifungal, antibacterial and anti-inflammatory effects, and acts as reducing and capping agents in this synthetic route. The tissue culture infectious dose (TCID50) assay showed that the curcumin modified silver nanoparticles (cAgNPs) have a highly efficient inhibition

Sugar-Terminated Nanoparticle Chaperones Are 102-105 Times Better Than Molecular Sugars in Inhibiting Protein Aggregation and Reducing Amyloidogenic Cytotoxicity.

PubMed

Pradhan, Nibedita; Shekhar, Shashi; Jana, Nihar R; Jana, Nikhil R

2017-03-29

Sugar-based osmolyte molecules are known to stabilize proteins under stress, but usually they have poor chaperone performance in inhibiting protein aggregation. Here, we show that the nanoparticle form of sugars molecule can enhance their chaperone performance typically by 10 2 -10 5 times, compared to molecular sugar. Sugar-based plate-like nanoparticles of 20-40 nm hydrodynamic size have been synthesized by simple heating of acidic aqueous solution of glucose/sucrose/maltose/trehalose. These nanoparticles have excitation-dependent green/yellow/orange emission and surface chemistry identical to the respective sugar molecule. Fibrillation of lysozyme/insulin/amyloid beta in extracellular space, aggregation of mutant huntingtin protein inside model neuronal cell, and cytotoxic effect of fibrils are investigated in the presence of these sugar nanoparticles. We found that sugar nanoparticles are 10 2 -10 5 times efficient than respective sugar molecules in inhibiting protein fibrillation and preventing cytotoxicity arising of fibrils. We propose that better performance of the nanoparticle form is linked to its stronger binding with fibril structure and enhanced cell uptake. This result suggests that nanoparticle form of osmolyte can be an attractive option in prevention and curing of protein aggregation-derived diseases.

Anthothecol-encapsulated PLGA nanoparticles inhibit pancreatic cancer stem cell growth by modulating sonic hedgehog pathway.

PubMed

Verma, Raj Kumar; Yu, Wei; Singh, Surya Pratap; Shankar, Sharmila; Srivastava, Rakesh K

2015-11-01

Anthothecol, a limonoid isolated from plant Khaya anthotheca (Meliaceae), is an antimalarial compound. The objectives of this study were to examine the molecular mechanisms by which anthothecol-encapsulated PLGA-nanoparticles (Antho-NPs) regulate the behavior of pancreatic cancer stem cells (CSCs). Antho-NPs inhibited cell proliferation and colony formation, and induced apoptosis in pancreatic CSCs and cancer cell lines, but had no effects on human normal pancreatic ductal epithelial cells. Antho-NPs inhibited self-renewal capacity of pancreatic CSCs isolated from human and Kras(G12D) mice. Furthermore, antho-NPs suppressed cell motility, migration and invasion by up-regulating E-cadherin and inhibiting N-cadherin and Zeb1. In addition, Antho-NPs inhibited pluripotency maintaining factors and stem cell markers, suggesting their inhibitory role on CSC population. Anthothecol disrupted binding of Gli to DNA, and inhibited Gli transcription and Gli target genes. Our studies establish preclinical significance of Antho-NPs for the treatment and/or prevention of pancreatic cancer. Despite medical advances, the prognosis of pancreatic cancer remains poor. The search for an effective treatment has been under intensive research for some time. In this article, the authors investigated the efficacy and mechanism of anthothecol (an antimalarial compound), encapsulated by PLGA nanoparticles (Antho-NPs), against pancreatic cancer cell lines. It was found that Antho-NPs acted via the Sonic hedgehog signaling pathway and inhibited cancer stem cell growth. These results have provided important basis for further clinical trials. Copyright © 2015 Elsevier Inc. All rights reserved.

Tumour angiogenesis is reduced in the Tc1 mouse model of Down's syndrome.

PubMed

Reynolds, Louise E; Watson, Alan R; Baker, Marianne; Jones, Tania A; D'Amico, Gabriela; Robinson, Stephen D; Joffre, Carine; Garrido-Urbani, Sarah; Rodriguez-Manzaneque, Juan Carlos; Martino-Echarri, Estefanía; Aurrand-Lions, Michel; Sheer, Denise; Dagna-Bricarelli, Franca; Nizetic, Dean; McCabe, Christopher J; Turnell, Andrew S; Kermorgant, Stephanie; Imhof, Beat A; Adams, Ralf; Fisher, Elizabeth M C; Tybulewicz, Victor L J; Hart, Ian R; Hodivala-Dilke, Kairbaan M

2010-06-10

Down's syndrome (DS) is a genetic disorder caused by full or partial trisomy of human chromosome 21 and presents with many clinical phenotypes including a reduced incidence of solid tumours. Recent work with the Ts65Dn model of DS, which has orthologues of about 50% of the genes on chromosome 21 (Hsa21), has indicated that three copies of the ETS2 (ref. 3) or DS candidate region 1 (DSCR1) genes (a previously known suppressor of angiogenesis) is sufficient to inhibit tumour growth. Here we use the Tc1 transchromosomic mouse model of DS to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses roughly 81% of Hsa21 genes but not the human DSCR1 region. We transplanted B16F0 and Lewis lung carcinoma tumour cells into Tc1 mice and showed that growth of these tumours was substantially reduced compared with wild-type littermate controls. Furthermore, tumour angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS1and ERG) and novel endothelial cell-specific genes, never previously shown to be involved in angiogenesis (JAM-B and PTTG1IP), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis, explaining the reduced tumour growth in DS. Furthermore, we expect that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will permit the identification of other endothelium-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients.

The mechanical microenvironment in cancer: How physics affects tumours.

PubMed

Nagelkerke, Anika; Bussink, Johan; Rowan, Alan E; Span, Paul N

2015-12-01

The tumour microenvironment contributes greatly to the response of tumour cells. It consists of chemical gradients, for example of oxygen and nutrients. However, a physical environment is also present. Apart from chemical input, cells also receive physical signals. Tumours display unique mechanical properties: they are a lot stiffer than normal tissue. This may be either a cause or a consequence of cancer, but literature suggests it has a major impact on tumour cells as will be described in this review. The mechanical microenvironment may cause malignant transformation, possibly through activation of oncogenic pathways and inhibition of tumour suppressor genes. In addition, the mechanical microenvironment may promote tumour progression by influencing processes such as epithelial-to-mesenchymal transition, enhancing cell survival through autophagy, but also affects sensitivity of tumour cells to therapeutics. Furthermore, multiple intracellular signalling pathways prove sensitive to the mechanical properties of the microenvironment. It appears the increased stiffness is unlikely to be caused by increased stiffness of the tumour cells themselves. However, there are indications that tumours display a higher cell density, making them more rigid. In addition, increased matrix deposition in the tumour, as well as increased interstitial fluid pressure may account for the increased stiffness of tumours. Overall, tumour mechanics are significantly different from normal tissue. Therefore, this feature should be further explored for use in cancer prevention, detection and treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours

PubMed Central

Tate, Sonya C; Burke, Teresa F; Hartman, Daisy; Kulanthaivel, Palaniappan; Beckmann, Richard P; Cronier, Damien M

2016-01-01

Background: Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the quantitative pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation. Methods: A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival. Results: The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression. Conclusions: The quantitative pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified. PMID:26978007

Quercetin conjugated with silica nanoparticles inhibits tumor growth in MCF-7 breast cancer cell lines.

PubMed

Aghapour, Fahimeh; Moghadamnia, Ali Akbar; Nicolini, Andrea; Kani, Seydeh Narges Mousavi; Barari, Ladan; Morakabati, Payam; Rezazadeh, Leyla; Kazemi, Sohrab

2018-06-12

Quercetin is a plant polyphenol from the flavonoid group that plays a fundamental role in controlling homeostasis due to its potent antioxidant properties. However, quercetin has extremely low water solubility, which is a major challenge in drug absorption. In this study, we described a simple method for the synthesis of quercetin nanoparticles. The quercetin nanoparticles had an average diameter of 82 nm and prominent yellow emission under UV irradiation. Therefore, we used an in vitro model treated with quercetin and quercetin nanoparticles to investigate the effects of quercetin nanoparticles on MCF-7 breast cancer cell line. MCF-7 cells were cultured with different concentrations (1-100 μM) of quercetin nanoparticles at the 24th, 48th and 72 nd hours, and cell cycle and apoptosis assays were detected by flow cytometry (FCM). In this study, we found that quercetin nanoparticles (1-100 μM) could significantly reduce cell vitality, growth rate and colony formation of MCF-7 cells. Quercetin nanoparticles can inhibit cell growth by blocking the cell cycle and promoting apoptosis in MCF-7 cells more than quercetin. As a result, quercetin nanoparticles may be useful therapy or prevention on breast cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

Partners in crime: VEGF and IL-4 conscript tumour-promoting macrophages.

PubMed

De Palma, Michele

2012-05-01

Tumour-associated macrophages (TAMs) foster tumour progression by several mechanisms, including the promotion of angiogenesis, tissue remodelling, and immunosuppression. Such pro-tumoural activities are thought to be executed by TAM subtypes that harbour features of alternatively activated (or M2-polarized) macrophages. However, the molecular signals in tumours that induce recruitment and differentiation of M2-like macrophages are not fully defined. In this issue of The Journal of Pathology, Linde et al investigate the role of the tumour-derived cytokines, VEGF and IL-4, in the recruitment and polarization of macrophages in a mouse model of skin cancer. The authors report that while VEGF-A recruits monocytes from the peripheral circulation, IL-4 induces their differentiation into tumour-promoting, M2-like macrophages. IL-4 signalling blockade was sufficient to reprogram TAMs away from the M2-like phenotype and inhibited tumour angiogenesis and growth. This study attests to the potential of reprogramming TAMs to abate their pro-angiogenic and pro-tumoural functions in tumours. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Inhibition of matrix metalloproteinases and toxicity of gold and platinum nanoparticles in L929 fibroblast cells.

PubMed

Hashimoto, Masanori; Yamaguchi, Satoshi; Sasaki, Jun-Ichi; Kawai, Koji; Kawakami, Hayato; Iwasaki, Yasuhiko; Imazato, Satoshi

2016-02-01

This study evaluated the inhibition of matrix metalloproteases (MMPs) and cellular responses elicited by gold (Au) and platinum (Pt) nanoparticles (NPs). The interaction of MMP-1 and NPs was evaluated using an MMP assay kit. The cultured L929 cells were exposed to various concentrations of NPs. The cellular responses to NPs were examined using a cytotoxicity assay (that evaluated cell viability and lactic dehydrogenase production), real-time polymerase chain reaction (RT-qPCR), and transmission electron microscopy. Both types of NPs, when used at concentrations above 10 μg ml(-1), inhibited MMP-1 activity. No cytotoxic effects were found when the cells were exposed to AuNPs. In contrast, PtNPs, at both 100 and 400 μg ml(-1), induced cytotoxicity. No inflammatory responses (production of interleukin-6 and tumor necrosis factor-alpha) to NPs were identified by RT-qPCR. The negative surface charge of NPs (COOH(-)) binds to the Zn(2+) of the MMP active center by chelation, leading to MMP inhibition. Gold nanoparticles are plausible candidates for MMP inhibitors in resin-bonding materials because they effectively inhibit MMP-1 activity without cytotoxic or inflammatory effects. © 2015 Eur J Oral Sci.

Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer

PubMed Central

Rao, S R; Snaith, A E; Marino, D; Cheng, X; Lwin, S T; Orriss, I R; Hamdy, F C; Edwards, C M

2017-01-01

Background: Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression. Methods: Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis. Results: ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival. Conclusions: Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression. PMID:28006818

Triptonide inhibits the pathological functions of gastric cancer-associated fibroblasts.

PubMed

Wang, Zhenfei; Ma, Daguang; Wang, Changshan; Zhu, Zhe; Yang, Yongyan; Zeng, Fenfang; Yuan, Jianlong; Liu, Xia; Gao, Yue; Chen, Yongxia; Jia, Yongfeng

2017-12-01

Direct attacks on tumour cells with chemotherapeutic drugs have the drawbacks of accelerating tumour metastasis and inducing tumour stem cell phenotypes. Inhibition of tumour-associated fibroblasts, which provide nourishment and support to tumour cells, is a novel and promising anti-tumour strategy. However, effective drugs against tumour-associated fibroblasts are currently lacking. In the present study, we explored the possibility of inhibiting the pathological functions of tumour-associated fibroblasts with triptonide. Paired gastric normal fibroblasts (GNFs) and gastric cancer-associated fibroblasts (GCAFs) were obtained from resected tissues. GCAFs showed higher capacities to induce colony formation, migration, and invasion of gastric cancer cells than GNFs. Triptonide treatment strongly inhibited the colony formation-, migration-, and invasion-promoting capacities of GCAFs. The expression of microRNA-301a was higher and that of microRNA-149 was lower in GCAFs than in GNFs. Triptonide treatment significantly down-regulated microRNA-301a expression and up-regulated microRNA-149 expression in GCAFs. Re-establishment of microRNA expression balance increased the production and secretion of tissue inhibitor of metalloproteinase 2, a tumour suppressive factor, and suppressed the production and secretion of IL-6, an oncogenic factor, in GCAFs. Moreover, triptonide treatment abolished the ability of GCAFs to induce epithelial-mesenchymal transition in gastric cancer cells. These results indicate that triptonide inhibits the malignancy-promoting capacity of GCAFs by correcting abnormalities in microRNA expression. Thus, triptonide is a promisingly therapeutic agent for gastric cancer treatment, and traditional herbs may be a valuable source for developing new drugs that can regulate the tumour microenvironment. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Inhibition by 6-mercaptopurine of purine phosphoribosyltransferases from Ehrlich ascites-tumour cells that are resistant to this drug

PubMed Central

Atkinson, M. R.; Murray, A. W.

1965-01-01

1. A strain of Ehrlich ascites-tumour cells that showed little inhibition of growth in the presence of 6-mercaptopurine accumulated less than 5% as much 6-thioinosine 5′-phosphate in vivo, in the presence of 6-mercaptopurine, as did the sensitive strain from which it was derived. 2. Specific activities of the phosphoribosyltransferases that convert adenine, guanine, hypoxanthine and 6-mercaptopurine into AMP, GMP, IMP and 6-thioinosine 5′-phosphate were similar in extracts of the resistant and the sensitive cells. 3. As found previously with sensitive cells, 6-mercaptopurine is a competitive inhibitor of guanine phosphoribosyltransferase and hypoxanthine phosphoribosyltransferase from the resistant cells and does not inhibit the adenine phosphoribosyltransferase from these cells. Michaelis constants and inhibitor constants of the purine phosphoribosyltransferases from resistant cells did not differ significantly from those measured with the corresponding enzymes from sensitive cells. 4. Resistance to 6-mercaptopurine in this case is probably not due to qualitative or quantitative changes in these transferases. PMID:14342251

Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer via p53/PRC1 pathway.

PubMed

Ye, Bai-Liang; Zheng, Ru; Ruan, Xiao-Jiao; Zheng, Zhi-Hai; Cai, Hua-Jie

2018-01-01

Nano-particles have been widely used in target-specific drug delivery system and showed advantages in cancers treatment. This study aims to evaluate the effect of chitosan coated doxorubicin nano-particles drug delivery system in liver cancer. The chitosan nano-particles were prepared by using the ionic gelation method. The characterizations of the nano-particles were determined by transmission electron microscopy. The cytotoxicity was detected by MTT assay, and the endocytosis, cell apoptosis and cell cycle were examined by flow cytometry. The protein level was analyzed with western blot. The dual luciferase reporter assay was performed to assess the interaction between p53 and the promoter of PRC1, and chromatin immune-precipitation was used to verify the binding between them. The FA-CS-DOX nano-particles were irregular and spherical particles around 30-40 nm, with uniform size and no adhesion. No significant difference was noted in doxorubicin release rate between CS-DOX and FA-CS-DOX. FA-CS-DOX nano-particles showed stronger cytotoxicity than CS-DOX. FA-CS-DOX nano-particles promoted the apoptosis and arrested cell cycle at G2/M phase, and they up-regulated p53. FA-CS-DOX nano-particles inhibited cell survival through p53/PRC1 pathway. Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer by promoting apoptosis and arresting cell cycle at G2/M phase through p53/PRC1 pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Magnetic nanoparticle-induced hyperthermia with appropriate payloads: Paul Ehrlich's "magic (nano)bullet" for cancer theranostics?

PubMed

Datta, N R; Krishnan, S; Speiser, D E; Neufeld, E; Kuster, N; Bodis, S; Hofmann, H

2016-11-01

Effective multimodal cancer management requires the optimal integration of diagnostic and therapeutic modalities. Radiation therapy, chemotherapy and immunotherapy, alone or in combination, are integral parts of various cancer treatment protocols. Hyperthermia at 39-45°C is a potent radiosensitiser and has been shown to improve therapeutic outcomes in various tumours through its synergy with chemotherapy. Gene silencing approaches, using small interfering RNAs and microRNAs, are also being explored in clinical trials in oncology. The rapid developments in multifunctional nanoparticles provide ample opportunities to integrate both diagnostic and therapeutic modalities into a single effective cancer "theranostic" vector. Nanoparticles could extravasate passively into the tumour tissues in preference to the adjacent normal tissues by capitalizing on the enhanced permeability and retention effect. Tumour targeting might be further augmented by conjugating tumour-specific peptides and antibodies onto the surface of these nanoparticles or by activation through electromagnetic radiations, laser or ultrasound. Magnetic nanoparticles can induce hyperthermia in the presence of an alternating magnetic field, thereby multifunctionally with tumour-specific payloads empowering tumour specific radiotheranostics (for both imaging and radiotherapy), chemotherapy drug delivery, immunotherapy and gene silencing therapy. Such a (nano)bullet could realise the "magic bullet" conceived by Paul Ehrlich more than a century ago. This article discusses the various aspects of this "magic (nano)bullet" and the challenges that need to be addressed to usher in this new paradigm in modern cancer diagnostics and therapeutics. Copyright © 2016 Elsevier Ltd. All rights reserved.

M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer

NASA Astrophysics Data System (ADS)

Ghosh, Debadyuti; Lee, Youjin; Thomas, Stephanie; Kohli, Aditya G.; Yun, Dong Soo; Belcher, Angela M.; Kelly, Kimberly A.

2012-10-01

Molecular imaging allows clinicians to visualize the progression of tumours and obtain relevant information for patient diagnosis and treatment. Owing to their intrinsic optical, electrical and magnetic properties, nanoparticles are promising contrast agents for imaging dynamic molecular and cellular processes such as protein-protein interactions, enzyme activity or gene expression. Until now, nanoparticles have been engineered with targeting ligands such as antibodies and peptides to improve tumour specificity and uptake. However, excessive loading of ligands can reduce the targeting capabilities of the ligand and reduce the ability of the nanoparticle to bind to a finite number of receptors on cells. Increasing the number of nanoparticles delivered to cells by each targeting molecule would lead to higher signal-to-noise ratios and would improve image contrast. Here, we show that M13 filamentous bacteriophage can be used as a scaffold to display targeting ligands and multiple nanoparticles for magnetic resonance imaging of cancer cells and tumours in mice. Monodisperse iron oxide magnetic nanoparticles assemble along the M13 coat, and its distal end is engineered to display a peptide that targets SPARC glycoprotein, which is overexpressed in various cancers. Compared with nanoparticles that are directly functionalized with targeting peptides, our approach improves contrast because each SPARC-targeting molecule delivers a large number of nanoparticles into the cells. Moreover, the targeting ligand and nanoparticles could be easily exchanged for others, making this platform attractive for in vivo high-throughput screening and molecular detection.

M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer.

PubMed

Ghosh, Debadyuti; Lee, Youjin; Thomas, Stephanie; Kohli, Aditya G; Yun, Dong Soo; Belcher, Angela M; Kelly, Kimberly A

2012-10-01

Molecular imaging allows clinicians to visualize the progression of tumours and obtain relevant information for patient diagnosis and treatment. Owing to their intrinsic optical, electrical and magnetic properties, nanoparticles are promising contrast agents for imaging dynamic molecular and cellular processes such as protein-protein interactions, enzyme activity or gene expression. Until now, nanoparticles have been engineered with targeting ligands such as antibodies and peptides to improve tumour specificity and uptake. However, excessive loading of ligands can reduce the targeting capabilities of the ligand and reduce the ability of the nanoparticle to bind to a finite number of receptors on cells. Increasing the number of nanoparticles delivered to cells by each targeting molecule would lead to higher signal-to-noise ratios and would improve image contrast. Here, we show that M13 filamentous bacteriophage can be used as a scaffold to display targeting ligands and multiple nanoparticles for magnetic resonance imaging of cancer cells and tumours in mice. Monodisperse iron oxide magnetic nanoparticles assemble along the M13 coat, and its distal end is engineered to display a peptide that targets SPARC glycoprotein, which is overexpressed in various cancers. Compared with nanoparticles that are directly functionalized with targeting peptides, our approach improves contrast because each SPARC-targeting molecule delivers a large number of nanoparticles into the cells. Moreover, the targeting ligand and nanoparticles could be easily exchanged for others, making this platform attractive for in vivo high-throughput screening and molecular detection.

Predicting thermal history a-priori for magnetic nanoparticle hyperthermia of internal carcinoma

NASA Astrophysics Data System (ADS)

Dhar, Purbarun; Sirisha Maganti, Lakshmi

2017-08-01

This article proposes a simplistic and realistic method where a direct analytical expression can be derived for the temperature field within a tumour during magnetic nanoparticle hyperthermia. The approximated analytical expression for thermal history within the tumour is derived based on the lumped capacitance approach and considers all therapy protocols and parameters. The present method is simplistic and provides an easy framework for estimating hyperthermia protocol parameters promptly. The model has been validated with respect to several experimental reports on animal models such as mice/rabbit/hamster and human clinical trials. It has been observed that the model is able to accurately estimate the thermal history within the carcinoma during the hyperthermia therapy. The present approach may find implications in a-priori estimation of the thermal history in internal tumours for optimizing magnetic hyperthermia treatment protocols with respect to the ablation time, tumour size, magnetic drug concentration, field strength, field frequency, nanoparticle material and size, tumour location, and so on.

Drug packaging and delivery using perfluorocarbon nanoparticles for targeted inhibition of vascular smooth muscle cells

PubMed Central

Zhou, Zhao-xiong; Zhang, Bai-gen; Zhang, Hao; Huang, Xiao-zhong; Hu, Ya-li; Sun, Li; Wang, Xiao-min; Zhang, Ji-wei

2009-01-01

Aim: To investigate the in vitro release profile of drugs encapsulated within perfluorocarbon (PFC) nanoparticles (NPs) and their ability to inhibit the activity of vascular smooth muscle cells (SMCs). Methods: Dexamethasone phosphate (DxP) or dexamethasone acetate (DxA) was encapsulated into PFC nanoparticles using a high-pressure homogenous method. The morphology and size of the NPs were examined using scanning electron microscopy (SEM) and a laser particle size analyzer. Drug loading and in vitro release were assessed by high-performance liquid chromatography (HPLC). The impact of NP capsules on SMC proliferation, migration and apoptosis in vitro was assessed using cell counting kit-8, transwell cell migration and flow cytometry assays. Results: The sizes of DxP-NPs and DxA-NPs were 224±6 nm and 236±9 nm, respectively. The encapsulation efficiency (EE) of DxP-NPs was 66.4%±1.0%, with an initial release rate of 77.2%, whereas the EE of DxA-NPs was 95.3%±1.3%, with an initial release rate of 23.6%. Both of the NP-coated drugs could be released over 7 d. Human umbilical artery SMCs were harvested and cultured for four to six passages. Compared to free DxP, SMCs treated with tissue factor (TF)-directed DxP-NPs showed significant differences in the inhibition of proliferation, migration and apoptosis (P<0.05). Conclusion: The results collectively suggest that PFC nanoparticles will be beneficial for targeted drug delivery because of the sustained drug release and effective inhibition of SMC proliferation and migration. PMID:19890365

Synthesis of magnetic composite nanoparticles enveloped in copolymers specified for scale inhibition application

NASA Astrophysics Data System (ADS)

Do, Bao Phuong Huu; Dung Nguyen, Ba; Duy Nguyen, Hoang; Nguyen, Phuong Tung

2013-12-01

We report the synthesis of magnetic iron oxide nanoparticles encapsulated in maleic acid-2-acrylamido-2-methyl-1-propanesulfonate based polymer. This composite nanoparticle is specified for the high-pressure/high-temperature (HPHT) oilfield scale inhibition application. The process includes a facile-ultrasound-supported addition reaction to obtain iron oxide nanoparticles with surface coated by oleic acid. Then via inverse microemulsion polymerization with selected monomers, the specifically designed copolymers have been formatted in nanoscale. The structure and morphology of obtained materials were characterized by transmission electron microscopy (TEM), x-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and the thermal stability. The effectiveness of synthesized compounds as a carbonate scale inhibitor was investigated by testing method NACE standard TM 03-074-95 at aging temperature of 70, 90 and 120 °C. The magnetic nanocomposite particles can be easily collected and detected demonstrating their superior monitoring ability, which is absent in the case of conventional copolymer-based scale inhibitor.

Gallium nanoparticles facilitate phagosome maturation and inhibit growth of virulent Mycobacterium tuberculosis in macrophages.

PubMed

Choi, Seoung-Ryoung; Britigan, Bradley E; Moran, David M; Narayanasamy, Prabagaran

2017-01-01

New treatments and novel drugs are required to counter the growing problem of drug-resistant strains of Mycobacterium tuberculosis (M.tb). Our approach against drug resistant M.tb, as well as other intracellular pathogens, is by targeted drug delivery using nanoformulations of drugs already in use, as well as drugs in development. Among the latter are gallium (III) (Ga)-based compounds. In the current work, six different types of Ga and rifampin nanoparticles were prepared in such a way as to enhance targeting of M.tb infected-macrophages. They were then tested for their ability to inhibit growth of a fully pathogenic strain (H37Rv) or a non-pathogenic strain (H37Ra) of M.tb. Encapsulating Ga in folate- or mannose-conjugated block copolymers provided sustained Ga release for 15 days and significantly inhibited M.tb growth in human monocyte-derived macrophages. Nanoformulations with dendrimers encapsulating Ga or rifampin also showed promising anti-tuberculous activity. The nanoparticles co-localized with M.tb containing phagosomes, as measured by detection of mature cathepsin D (34 kDa, lysosomal hydrogenase). They also promoted maturation of the phagosome, which would be expected to increase macrophage-mediated killing of the organism. Delivery of Ga or rifampin in the form of nanoparticles to macrophages offers a promising approach for the development of new therapeutic anti-tuberculous drugs.

Gallium nanoparticles facilitate phagosome maturation and inhibit growth of virulent Mycobacterium tuberculosis in macrophages

PubMed Central

Choi, Seoung-ryoung; Britigan, Bradley E.; Moran, David M.

2017-01-01

New treatments and novel drugs are required to counter the growing problem of drug-resistant strains of Mycobacterium tuberculosis (M.tb). Our approach against drug resistant M.tb, as well as other intracellular pathogens, is by targeted drug delivery using nanoformulations of drugs already in use, as well as drugs in development. Among the latter are gallium (III) (Ga)-based compounds. In the current work, six different types of Ga and rifampin nanoparticles were prepared in such a way as to enhance targeting of M.tb infected-macrophages. They were then tested for their ability to inhibit growth of a fully pathogenic strain (H37Rv) or a non-pathogenic strain (H37Ra) of M.tb. Encapsulating Ga in folate- or mannose-conjugated block copolymers provided sustained Ga release for 15 days and significantly inhibited M.tb growth in human monocyte-derived macrophages. Nanoformulations with dendrimers encapsulating Ga or rifampin also showed promising anti-tuberculous activity. The nanoparticles co-localized with M.tb containing phagosomes, as measured by detection of mature cathepsin D (34 kDa, lysosomal hydrogenase). They also promoted maturation of the phagosome, which would be expected to increase macrophage-mediated killing of the organism. Delivery of Ga or rifampin in the form of nanoparticles to macrophages offers a promising approach for the development of new therapeutic anti-tuberculous drugs. PMID:28542623

Tumour angiogenesis is reduced in the Tc1 mouse model of Down Syndrome

PubMed Central

Reynolds, Louise E.; Watson, Alan R.; Baker, Marianne; Jones, Tania A.; D’Amico, Gabriela; Robinson, Stephen D.; Joffre, Carine; Garrido-Urbani, Sarah; Rodriguez-Manzaneque, Juan Carlos; Martino-Echarri, Estefanía; Aurrand-Lions, Michel; Sheer, Denise; Dagna-Bricarelli, Franca; Nizetic, Dean; McCabe, Christopher J.; Turnell, Andrew S.; Kermorgant, Stephanie; Imhof, Beat A.; Adams, Ralf; Fisher, Elizabeth M.C.; Tybulewicz, Victor L. J.; Hart, Ian R.; Hodivala-Dilke, Kairbaan M.

2012-01-01

Down Syndrome (DS) is a genetic disorder caused by full or partial trisomy of chromosome 21. It occurs in approximately 1/750 live births and presents with many clinical phenotypes including a reduced incidence of solid tumours1,2. Recent work using the Ts65Dn model of DS, that has orthologs of approximately 50% of the genes on human chromosome 21 (Hsa21), has suggested that three copies of the ETS23 or Down Syndrome candidate region 1 (DSCR1) genes4 (a previously known suppressor of angiogenesis5,6) is sufficient to inhibit tumour growth. We have used the Tc1 transchromosomic mouse model of DS9 to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses approximately 81% of Hsa21 genes but not the human DSCR1 region (Supplementary Fig. 1). We transplanted B16F0 and Lewis Lung Carcinoma (LLC) tumour cells into Tc1 mice and showed that growth of these tumours was reduced substantially when compared to wild-type littermate controls. Furthermore, tumour angiogenesis was repressed significantly in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS17,8 and ERG9) and novel endothelial cell-specific genes10, never shown before to be involved in angiogenesis (JAM-B11 and PTTG1IP) that, when overexpressed, are responsible for the inhibition of angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis providing an explanation for the reduced tumour growth in DS. Furthermore, we anticipate that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will likely allow for the identification of other endothelial-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients. PMID:20535211

Local administration of curcumin-loaded nanoparticles effectively inhibits inflammation and bone resorption associated with experimental periodontal disease.

PubMed

Zambrano, Laura M G; Brandao, Dayane A; Rocha, Fernanda R G; Marsiglio, Raquel P; Longo, Ieda B; Primo, Fernando L; Tedesco, Antonio C; Guimaraes-Stabili, Morgana R; Rossa Junior, Carlos

2018-04-27

There is evidence indicating that curcumin has multiple biological activities, including anti-inflammatory properties. In vitro and in vivo studies demonstrate that curcumin may attenuate inflammation and the connective tissue destruction associated with periodontal disease. Most of these studies use systemic administration, and considering the site-specific nature of periodontal disease and also the poor pharmacodynamic properties of curcumin, we conducted this proof of principle study to assess the biological effect of the local administration of curcumin in a nanoparticle vehicle on experimental periodontal disease. We used 16 rats divided into two groups of 8 animals according to the induction of experimental periodontal disease by bilateral injections of LPS or of the vehicle control directly into the gingival tissues 3×/week for 4 weeks. The same volume of curcumin-loaded nanoparticles or of nanoparticle vehicle was injected into the same sites 2×/week. µCT analysis showed that local administration of curcumin resulted in a complete inhibition of inflammatory bone resorption and in a significant decrease of both osteoclast counts and of the inflammatory infiltrate; as well as a marked attenuation of p38 MAPK and NF-kB activation. We conclude that local administration of curcumin-loaded nanoparticles effectively inhibited inflammation and bone resorption associated with experimental periodontal disease.

A novel individual-cell-based mathematical model based on multicellular tumour spheroids for evaluating doxorubicin-related delivery in avascular regions.

PubMed

Liu, Jiali; Yan, Fangrong; Chen, Hongzhu; Wang, Wenjie; Liu, Wenyue; Hao, Kun; Wang, Guangji; Zhou, Fang; Zhang, Jingwei

2017-09-01

Effective drug delivery in the avascular regions of tumours, which is crucial for the promising antitumour activity of doxorubicin-related therapy, is governed by two inseparable processes: intercellular diffusion and intracellular retention. To accurately evaluate doxorubicin-related delivery in the avascular regions, these two processes should be assessed together. Here we describe a new approach to such an assessment. An individual-cell-based mathematical model based on multicellular tumour spheroids was developed that describes the different intercellular diffusion and intracellular retention kinetics of doxorubicin in each cell layer. The different effects of a P-glycoprotein inhibitor (LY335979) and a hypoxia inhibitor (YC-1) were quantitatively evaluated and compared, in vitro (tumour spheroids) and in vivo (HepG2 tumours in mice). This approach was further tested by evaluating in these models, an experimental doxorubicin derivative, INNO 206, which is in Phase II clinical trials. Inhomogeneous, hypoxia-induced, P-glycoprotein expression compromised active transport of doxorubicin in the central area, that is, far from the vasculature. LY335979 inhibited efflux due to P-glycoprotein but limited levels of doxorubicin outside the inner cells, whereas YC-1 co-administration specifically increased doxorubicin accumulation in the inner cells without affecting the extracellular levels. INNO 206 exhibited a more effective distribution profile than doxorubicin. The individual-cell-based mathematical model accurately evaluated and predicted doxorubicin-related delivery and regulation in the avascular regions of tumours. The described framework provides a mechanistic basis for the proper development of doxorubicin-related drug co-administration profiles and nanoparticle development and could avoid unnecessary clinical trials. © 2017 The British Pharmacological Society.

Ganoderma lucidum total triterpenes attenuate DLA induced ascites and EAC induced solid tumours in Swiss albino mice.

PubMed

Smina, T P; Mathew, J; Janardhanan, K K

2016-04-30

G. lucidum total triterpenes were assessed for its apoptosis-inducing and anti-tumour activities. The ability of the total triterpenes to induce apoptosis was evaluated in Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines. Total triterpenes were found to be highly cytotoxic to DLA and EAC cell lines with IC50 values 5 ± 0.32 and 7.9 ± 0.2 µg/ml respectively. Total triterpenes induced apoptosis in both cell lines which is evident from the DNA fragmentation assay. Anti-tumour activity was accessed using DLA induced solid and EAC induced ascites tumour models in Swiss albino mice. Administration of 10, 50 and 100 mg/kg b. wt. total triterpenes showed 11.86, 27.27 and 40.57% increase in life span of animals in ascites tumour model. Treatment with 10, 50 and 100 mg/kg b. wt. total triterpenes exhibited 76.86, 85.01 and 91.03% inhibition in tumour volume and 67.96, 72.38 and 77.90% inhibition in tumour weight respectively in the solid tumour model. The study reveals the significant dose-dependent anti-tumour activity of total triterpenes in both models. Total triterpenes were more active against the solid tumour than the ascites tumour. The anti-oxidant potential and ability to induce cell-specific apoptosis could be contributing to its anti-tumour activities.

Association of reduction of AFB1-induced liver tumours by antioxidants with increased activity of microsomal enzymes.

PubMed

Nyandieka, H S; Wakhis, J; Kilonzo, M M

1990-10-01

The influence of nutritional factors on aflatoxin B1 (AFB1)-induced liver tumours was investigated in rats. When a dose of 500 micrograms AFB1/kg body weight was given to rats in the absence of any anticarcinogen, 80 per cent of the rats developed liver tumours as compared to 0 to 40 per cent in those which received anticarcinogens. While beta-carotene totally inhibited the development of liver tumours ascorbic acid, selenium, and uric acid reduced the percentages of tumour-bearing rats to 13 per cent each. GSH and vitamin E also reduced these percentages to 20 and 40 per cent respectively. The reduction of tumour incidence by each anticarcinogen was associated with induction of increased microsomal enzyme activity. Inhibition of AFB1-induced liver cancer development thus seems to occur through microsomal enzyme induction and AFB1 activation.

Direct anti-metastatic efficacy by the DNA enzyme Dz13 and downregulated MMP-2, MMP-9 and MT1-MMP in tumours

PubMed Central

2010-01-01

The DNA enzyme Dz13, targeted against the oncogene c-Jun, is capable of inhibiting various model tumours in mice albeit in ectopic models of neoplasia. In previous studies using orthotopic models of disease, the inhibitory effects of Dz13 on secondary growth was a direct result of growth inhibition at the primary lesion site. Thus, the direct and genuine effects on metastasis were not gauged. In this study, Dz13 was able to inhibit both locoregional and distal metastasis of tumour cells in mice, in studies where the primary tumours were unaffected due to the late and clinically-mimicking nature of treatment commencement. In addition, the effect of Dz13 against tumours has now been extended to encompass breast and prostate cancer. Dz13 upregulated the matrix metalloproteinase (MMP)-2 and MMP-9, and decreased expression of MT1-MMP (MMP-14) in cultured tumour cells. However, in sections of ectopic tumours treated with Dz13, both MMP-2 and MMP-9 were downregulated. Thus, not only is Dz13 able to inhibit tumour growth at the primary site, but also able to decrease the ability of neoplastic cells to metastasise. These findings further highlight the growing potential of Dz13 as an antineoplastic agent. PMID:20334687

AMP kinase promotes glioblastoma bioenergetics and tumour growth.

PubMed

Chhipa, Rishi Raj; Fan, Qiang; Anderson, Jane; Muraleedharan, Ranjithmenon; Huang, Yan; Ciraolo, Georgianne; Chen, Xiaoting; Waclaw, Ronald; Chow, Lionel M; Khuchua, Zaza; Kofron, Matthew; Weirauch, Matthew T; Kendler, Ady; McPherson, Christopher; Ratner, Nancy; Nakano, Ichiro; Dasgupta, Nupur; Komurov, Kakajan; Dasgupta, Biplab

2018-06-18

Stress is integral to tumour evolution, and cancer cell survival depends on stress management. We found that cancer-associated stress chronically activates the bioenergetic sensor AMP kinase (AMPK) and, to survive, tumour cells hijack an AMPK-regulated stress response pathway conserved in normal cells. Analysis of The Cancer Genome Atlas data revealed that AMPK isoforms are highly expressed in the lethal human cancer glioblastoma (GBM). We show that AMPK inhibition reduces viability of patient-derived GBM stem cells (GSCs) and tumours. In stressed (exercised) skeletal muscle, AMPK is activated to cooperate with CREB1 (cAMP response element binding protein-1) and promote glucose metabolism. We demonstrate that oncogenic stress chronically activates AMPK in GSCs that coopt the AMPK-CREB1 pathway to coordinate tumour bioenergetics through the transcription factors HIF1α and GABPA. Finally, we show that adult mice tolerate systemic deletion of AMPK, supporting the use of AMPK pharmacological inhibitors in the treatment of GBM.

DNA-mediated inhibition of peroxidase-like activities on platinum nanoparticles for simple and rapid colorimetric detection of nucleic acids.

PubMed

Chen, Weiwei; Fang, Xueen; Li, Hua; Cao, Hongmei; Kong, Jilie

2017-08-15

In this research, we found that the peroxidase-like activities of noncovalent DNA-Pt hybrid nanoparticles could be obviously blocked, when Pt nanoparticles (PtNPs) were synthesized in situ using DNA as a template. Moreover, this self-assembled synthetic process was very convenient and rapid (within few mintues), and the inhibition mediated by DNA was also very effective. First, by the paper-based analytical device (PAD) we found the catalytic activities of DNA-Pt hybrid nanoparticles exhibited a linear response to the concentration of DNA in the range from 0.0075 to 0.25µM. Then, with the magnetic bead isolated system and target DNA-induced hybridization chain reaction (HCR), we realized the specific target DNA analysis with a low detection of 0.228nM, and demonstrated its effectivity in distinguishing the target DNA from other interferences. To our knowledge, this is the first report that used the nanoassembly between DNA and PtNPs for colorimetric detection of nucleic acids, which was based on DNA-mediated inhibition of catalytic activities of platinum nanoparticles. The results may be useful for understanding the interactions between DNA and metal nanoparticles, and for development of other convenient and effective analytical strategies. Copyright © 2017. Published by Elsevier B.V.

Effect of chitosan and thiolated chitosan coating on the inhibition behaviour of PIBCA nanoparticles against intestinal metallopeptidases

NASA Astrophysics Data System (ADS)

Bravo-Osuna, Irene; Vauthier, Christine; Farabollini, Alessandra; Millotti, Gioconda; Ponchel, Gilles

2008-12-01

Surface modified nanoparticles composed of poly(isobutylcyanoacrylate) (PIBCA) cores surrounded by a chitosan and thiolated chitosan gel layer were prepared and characterized in previous works. The presence of such biopolymers on the nanoparticle surface conferred those nanosystems interesting characteristics that might partially overcome the gastrointestinal enzymatic barrier, improving the oral administration of pharmacologically active peptides. In the present work, the antiprotease behaviour of this family of core-shell nanoparticles was in vitro tested against two model metallopeptidases present in the gastrointestinal tract (GIT): Carboxypeptidase A -CP A- (luminal protease) and Leucine Aminopeptidase M -LAP M- (membrane protease). As previous step, the zinc-binding capacity of these nanoparticles was evaluated. Interestingly, an improvement of both the zinc-binding capacity and the antiprotease effect of chitosan was observed when the biopolymers (chitosan and thiolated chitosan) were used as coating component of the core-shell nanoparticles, in comparison with their behaviour in solution, thanks to the different biopolymer chains rearrangement. The presence of amino, hydroxyl and thiol groups on the nanoparticle surface promoted zinc binding and hence the inhibition of the metallopeptidases analysed. On the contrary, the occurrence of a cross-linked structure in the gel layer surrounding the PIBCA cores of thiolated formulations, due to the formation of interchain and intrachain disulphide bonds, partially limited the inhibition of the proteases. The low accessibility of cations to the active groups of the cross-linked polymeric shell was postulated as a possible explanation of this behaviour. Results obtained in this work make this family of surface-modified nanocarriers promising candidates for the successfull administration of pharmacologically active peptides and proteins by the oral route.

M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer

PubMed Central

Ghosh, Debadyuti; Lee, Youjin; Thomas, Stephanie; Kohli, Aditya G.; Yun, Dong Soo; Belcher, Angela M.; Kelly, Kimberly A.

2014-01-01

Molecular imaging allows clinicians to visualize the progression of tumours and obtain relevant information for patient diagnosis and treatment1. Owing to their intrinsic optical, electrical and magnetic properties, nanoparticles are promising contrast agents for imaging dynamic molecular and cellular processes such as protein-protein interactions, enzyme activity or gene expression2. Until now, nanoparticles have been engineered with targeting ligands such as antibodies and peptides to improve tumour specificity and uptake. However, excessive loading of ligands can reduce the targeting capabilities of the ligand3,4,5 and reduce the ability of the nanoparticle to bind to a finite number of receptors on cells6. Increasing the number of nanoparticles delivered to cells by each targeting molecule would lead to higher signal-to-noise ratios and improve image contrast. Here, we show that M13 filamentous bacteriophage can be used as a scaffold to display targeting ligands and multiple nanoparticles for magnetic resonance imaging of cancer cells and tumours in mice. Monodisperse iron oxide magnetic nanoparticles assemble along the M13 coat, and its distal end is engineered to display a peptide that targets SPARC glycoprotein, which is overexpressed in various cancers. Compared with nanoparticles that are directly functionalized with targeting peptides, our approach improves contrast because each SPARC-targeting molecule delivers a large number of nanoparticles into the cells. Moreover, the targeting ligand and nanoparticles could be easily exchanged for others, making this platform attractive for in vivo high-throughput screening and molecular detection. PMID:22983492

Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment.

PubMed

Yu, Hua; Kortylewski, Marcin; Pardoll, Drew

2007-01-01

Immune cells in the tumour microenvironment not only fail to mount an effective anti-tumour immune response, but also interact intimately with the transformed cells to promote oncogenesis actively. Signal transducer and activator of transcription 3 (STAT3), which is a point of convergence for numerous oncogenic signalling pathways, is constitutively activated both in tumour cells and in immune cells in the tumour microenvironment. Constitutively activated STAT3 inhibits the expression of mediators necessary for immune activation against tumour cells. Furthermore, STAT3 activity promotes the production of immunosuppressive factors that activate STAT3 in diverse immune-cell subsets, altering gene-expression programmes and, thereby, restraining anti-tumour immune responses. As such, STAT3 propagates several levels of crosstalk between tumour cells and their immunological microenvironment, leading to tumour-induced immunosuppression. Consequently, STAT3 has emerged as a promising target for cancer immunotherapy.

Hamamelitannin from Hamamelis virginiana inhibits the tumour necrosis factor-alpha (TNF)-induced endothelial cell death in vitro.

PubMed

Habtemariam, Solomon

2002-01-01

The tumour necrosis factor-alpha (TNF) inhibitory activity of hamamelitannin from Hamamelis virginiana was investigated by assessing the TNF-mediated EAhy926 endothelial cell death and adhesiveness to monocytes. Treatment of the cells by TNF (25 ng/ml) and actinomycin D (0.1ng/ml) resulted in significant DNA fragmentation (34+/-0.6, n=4) and cytotoxicity (97+/-4.5%, n=6) following treatment for 8 and 24h, respectively. One to 100 microM concentrations of hamamelitannin inhibited the TNF-mediated endothelial cell death and DNA fragmentation in a dose-dependent manner. One hundred % protection against TNF-induced DNA fragmentation and cytotoxicity was obtained for hamamelitannin concentrations higher than 10 microM. The protective effect of hamamelitannin was comparable with that of a related compound epigallocatechin gallate while gallic acid was a weak protective agent (<40% protection). EAhy926 endothelial cells upregulated (by 4- to 7-fold) the surface expression of intercellular adhesion molecule-1 (ICAM-1) and adhesiveness to monocytic U937 cells after treatment with TNF (0.5ng/ml) for 6 or 24h. Concentrations (1-100 microM) of hamamelitannin that inhibited the TNF-mediated cell death and DNA fragmentation, however, failed to inhibit the TNF-induced ICAM-1 expression and EAhy926 cell adhesiveness to U937 cells. Thus, hamamelitannin inhibits the TNF-mediated endothelial cell death without altering the TNF-induced upregulation of endothelial adhesiveness. The observed anti-TNF activity of hamamelitannin may explain the antihamorrhaegic use of H. virginiana in traditional medicine and its claimed use as a protective agent for UV radiation.

Intralymphatic mRNA vaccine induces CD8 T-cell responses that inhibit the growth of mucosally located tumours

PubMed Central

Bialkowski, Lukasz; van Weijnen, Alexia; Van der Jeught, Kevin; Renmans, Dries; Daszkiewicz, Lidia; Heirman, Carlo; Stangé, Geert; Breckpot, Karine; Aerts, Joeri L.; Thielemans, Kris

2016-01-01

The lack of appropriate mouse models is likely one of the reasons of a limited translational success rate of therapeutic vaccines against cervical cancer, as rapidly growing ectopic tumours are commonly used for preclinical studies. In this work, we demonstrate that the tumour microenvironment of TC-1 tumours differs significantly depending on the anatomical location of tumour lesions (i.e. subcutaneously, in the lungs and in the genital tract). Our data demonstrate that E7-TriMix mRNA vaccine-induced CD8+ T lymphocytes migrate into the tumour nest and control tumour growth, although they do not express mucosa-associated markers such as CD103 or CD49a. We additionally show that despite the presence of the antigen-specific T cells in the tumour lesions, the therapeutic outcomes in the genital tract model remain limited. Here, we report that such a hostile tumour microenvironment can be reversed by cisplatin treatment, leading to a complete regression of clinically relevant tumours when combined with mRNA immunization. We thereby demonstrate the necessity of utilizing clinically relevant models for preclinical evaluation of anticancer therapies and the importance of a simultaneous combination of anticancer immune response induction with targeting of tumour environment. PMID:26931556

Synthesis of biocompatible nanoparticle drug complexes for inhibition of mycobacteria

NASA Astrophysics Data System (ADS)

Bhave, Tejashree; Ghoderao, Prachi; Sanghavi, Sonali; Babrekar, Harshada; Bhoraskar, S. V.; Ganesan, V.; Kulkarni, Anjali

2013-12-01

Tuberculosis (TB) is one of the most critical infectious diseases affecting the world today. Current TB treatment involves six months long daily administration of four oral doses of antibiotics. Due to severe side effects and the long treatment, a patient's adherence is low and this results in relapse of symptoms causing an alarming increase in the prevalence of multi-drug resistant (MDR) TB. Hence, it is imperative to develop a new drug delivery technology wherein these effects can be reduced. Rifampicin (RIF) is one of the widely used anti-tubercular drugs (ATD). The present study discusses the development of biocompatible nanoparticle-RIF complexes with superior inhibitory activity against both Mycobacterium smegmatis (M. smegmatis) and Mycobacterium tuberculosis (M. tuberculosis). Iron oxide nanoparticles (NPs) synthesized by gas phase condensation and NP-RIF complexes were tested against M. smegmatis SN2 strain as well as M. tuberculosis H37Rv laboratory strain. These complexes showed significantly better inhibition of M. smegmatis SN2 strain at a much lower effective concentration (27.5 μg ml-1) as compared to neat RIF (125 μg ml-1). Similarly M. tuberculosis H37Rv laboratory strain was susceptible to both nanoparticle-RIF complex and neat RIF at a minimum inhibitory concentration of 0.22 and 1 μg ml-1, respectively. Further studies are underway to determine the efficacy of NPs-RIF complexes in clinical isolates of M. tuberculosis as well as MDR isolates.

Reactive Oxygen Species Mediated Bacterial Biofilm Inhibition via Zinc Oxide Nanoparticles and Their Statistical Determination

PubMed Central

Dwivedi, Sourabh; Wahab, Rizwan; Khan, Farheen; Mishra, Yogendra K.; Musarrat, Javed; Al-Khedhairy, Abdulaziz A.

2014-01-01

The formation of bacterial biofilm is a major challenge in clinical applications. The main aim of this study is to describe the synthesis, characterization and biocidal potential of zinc oxide nanoparticles (NPs) against bacterial strain Pseudomonas aeruginosa. These nanoparticles were synthesized via soft chemical solution process in a very short time and their structural properties have been investigated in detail by using X-ray diffraction and transmission electron microscopy measurements. In this work, the potential of synthesized ZnO-NPs (∼10–15 nm) has been assessed in-vitro inhibition of bacteria and the formation of their biofilms was observed using the tissue culture plate assays. The crystal violet staining on biofilm formation and its optical density revealed the effect on biofilm inhibition. The NPs at a concentration of 100 µg/mL significantly inhibited the growth of bacteria and biofilm formation. The biofilm inhibition by ZnO-NPs was also confirmed via bio-transmission electron microscopy (Bio-TEM). The Bio-TEM analysis of ZnO-NPs treated bacteria confirmed the deformation and damage of cells. The bacterial growth in presence of NPs concluded the bactericidal ability of NPs in a concentration dependent manner. It has been speculated that the antibacterial activity of NPs as a surface coating material, could be a feasible approach for controlling the pathogens. Additionally, the obtained bacterial solution data is also in agreement with the results from statistical analytical methods. PMID:25402188

Reactive oxygen species mediated bacterial biofilm inhibition via zinc oxide nanoparticles and their statistical determination.

PubMed

Dwivedi, Sourabh; Wahab, Rizwan; Khan, Farheen; Mishra, Yogendra K; Musarrat, Javed; Al-Khedhairy, Abdulaziz A

2014-01-01

The formation of bacterial biofilm is a major challenge in clinical applications. The main aim of this study is to describe the synthesis, characterization and biocidal potential of zinc oxide nanoparticles (NPs) against bacterial strain Pseudomonas aeruginosa. These nanoparticles were synthesized via soft chemical solution process in a very short time and their structural properties have been investigated in detail by using X-ray diffraction and transmission electron microscopy measurements. In this work, the potential of synthesized ZnO-NPs (∼ 10-15 nm) has been assessed in-vitro inhibition of bacteria and the formation of their biofilms was observed using the tissue culture plate assays. The crystal violet staining on biofilm formation and its optical density revealed the effect on biofilm inhibition. The NPs at a concentration of 100 µg/mL significantly inhibited the growth of bacteria and biofilm formation. The biofilm inhibition by ZnO-NPs was also confirmed via bio-transmission electron microscopy (Bio-TEM). The Bio-TEM analysis of ZnO-NPs treated bacteria confirmed the deformation and damage of cells. The bacterial growth in presence of NPs concluded the bactericidal ability of NPs in a concentration dependent manner. It has been speculated that the antibacterial activity of NPs as a surface coating material, could be a feasible approach for controlling the pathogens. Additionally, the obtained bacterial solution data is also in agreement with the results from statistical analytical methods.

Synthesis and characterization of fluorinated magnetic core-shell nanoparticles for inhibition of insulin amyloid fibril formation

NASA Astrophysics Data System (ADS)

Skaat, Hadas; Belfort, Georges; Margel, Shlomo

2009-06-01

Maghemite (γ-Fe2O3) magnetic nanoparticles of 15.0 ± 2.1 nm are formed by nucleation followed by controlled growth of maghemite thin films on gelatin-iron oxide nuclei. Uniform magnetic γ-Fe2O3/poly (2,2,3,3,4,4,4-heptafluorobutyl acrylate) (γ-Fe2O3/PHFBA) core-shell nanoparticles are prepared by emulsion polymerization of the fluorinated monomer 2,2,3,3,4,4,4-heptafluorobutyl acrylate (HFBA) in the presence of the maghemite nanoparticles. The kinetics of the insulin fibrillation process in the absence and in the presence of the γ-Fe2O3/PHFBA core-shell nanoparticles are elucidated. A significant direct slow transition from α-helix to β-sheets during insulin fibril formation is observed in the presence of the γ-Fe2O3/PHFBA nanoparticles. This is in contradiction to our previous manuscript, which illustrated that the γ-Fe2O3 core nanoparticles do not affect the kinetics of the formation of the insulin fibrils, and to other previous publications that describe acceleration of the fibrillation process by using various types of nanoparticles. These core-shell nanoparticles may therefore be also useful for the inhibition of conformational changes of other amyloidogenic proteins that lead to neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, mad cow and prion diseases.

Blocking CLEC14A-MMRN2 binding inhibits sprouting angiogenesis and tumour growth

PubMed Central

PJ, Noy; P, Lodhia; K, Khan; X, Zhuang; DG, Ward; AR, Verissimo; A, Bacon; R, Bicknell

2015-01-01

We previously identified CLEC14A as a tumour endothelial marker. Here we show CLEC14A is a regulator of sprouting angiogenesis in vitro and in vivo. Using a HUVEC spheroid sprouting assay we found CLEC14A to be a regulator of sprout initiation. Analysis of endothelial sprouting in aortic ring and in vivo subcutaneous sponge assays from clec14a+/+ and clec14a−/− mice revealed defects in sprouting angiogenesis in CLEC14A deficient animals. Tumour growth was retarded and vascularity reduced in clec14a−/− mice. Pulldown and co-immunoprecipitation experiments confirmed MMRN2 binds to the extracellular region of CLEC14A. The CLEC14A-MMRN2 interaction was interrogated using mouse monoclonal antibodies. Monoclonal antibodies were screened for their ability to block this interaction. Clone C4 but not C2 blocked CLEC14A-MMRN2 binding. C4 antibody perturbed tube formation and endothelial sprouting in vitro and in vivo, with a similar phenotype to loss of CLEC14A. Significantly, tumour growth was impaired in C4 treated animals and vascular density was also reduced in the C4 treated group. We conclude that CLEC14A-MMRN2 binding has a role in inducing sprouting angiogenesis during tumour growth, that has the potential to be manipulated in future anti-angiogenic therapy design. PMID:25745997

Overexpression of PBK/TOPK relates to tumour malignant potential and poor outcome of gastric carcinoma

PubMed Central

Ohashi, Takuma; Komatsu, Shuhei; Ichikawa, Daisuke; Miyamae, Mahito; Okajima, Wataru; Imamura, Taisuke; Kiuchi, Jun; Kosuga, Toshiyuki; Konishi, Hirotaka; Shiozaki, Atsushi; Fujiwara, Hitoshi; Okamoto, Kazuma; Tsuda, Hitoshi; Otsuji, Eigo

2017-01-01

Background: PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) is a serine–threonine kinase and overexpressed in various types of cancer by inhibiting the transactivation activities of p53 and PTEN. We tested whether PBK/TOPK acts as a cancer-promoting gene through its activation/overexpression in gastric cancer (GC). Methods: We analysed five GC cell lines and 144 primary tumours, which were curatively resected in our hospital between 2001 and 2003. Results: Overexpression of the PBK/TOPK protein was frequently detected in GC cell lines (4 out of 5 lines, 80.0%) was detected in primary tumour samples of GC (24 out of 144 cases, 16.6%) and was significantly correlated with venous invasion, tumour depth and recurrence rate. PDZ-binding kinase/T-LAK cell-originated protein kinase-overexpressing tumours had a worse survival rate than those with non-expressing tumours (P=0.0009, log-rank test). PDZ-binding kinase/T-LAK cell-originated protein kinase positivity was independently associated with a worse outcome in multivariate analysis (P<0.0001, hazard ratio 6.40 (2.71–14.49)). In PBK/TOPK-overexpressing GC cells, knockdown of PBK/TOPK inhibited the cell proliferation through the p53 activation in a TP53 mutation-dependent manner and inhibited the migration/invasion through the PTEN upregulation in a TP53 mutation-independent manner. Conclusions: These findings suggest PBK/TOPK plays a crucial role in tumour malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC. PMID:27898655

Multimodality cellular and molecular imaging of concomitant tumour enhancement in a syngeneic mouse model of breast cancer metastasis.

PubMed

Parkins, Katie M; Dubois, Veronica P; Hamilton, Amanda M; Makela, Ashley V; Ronald, John A; Foster, Paula J

2018-06-12

The mechanisms that influence metastatic growth rates are poorly understood. One mechanism of interest known as concomitant tumour resistance (CTR) can be defined as the inhibition of metastasis by existing tumour mass. Conversely, the presence of a primary tumour has also been shown to increase metastatic outgrowth, termed concomitant tumour enhancement (CTE). The majority of studies evaluating CTR/CTE in preclinical models have relied on endpoint histological evaluation of tumour burden. The goal of this research was to use conventional magnetic resonance imaging (MRI), cellular MRI, and bioluminescence imaging to study the impact of a primary tumour on the development of brain metastases in a syngeneic mouse model. Here, we report that the presence of a 4T1 primary tumour significantly enhances total brain tumour burden in Balb/C mice. Using in vivo BLI/MRI we could determine this was not related to differences in initial arrest or clearance of viable cells in the brain, which suggests that the presence of a primary tumour can increase the proliferative growth of brain metastases in this model. The continued application of our longitudinal cellular and molecular imaging tools will yield a better understanding of the mechanism(s) by which this physiological inhibition (CTR) and/or enhancement (CTE) occurs.

When does a strategy intervention overcome a failure of inhibition? Evidence from two left frontal brain tumour cases.

PubMed

Robinson, Gail A; Walker, David G; Biggs, Vivien; Shallice, Tim

2016-06-01

Initiation and inhibition of responses are crucial for appropriate behaviour across different settings. Initiation and inhibition difficulties are well documented following frontal damage, although task differences have limited our understanding. The Hayling Sentence Completion Test was designed to assess verbal initiation and inhibition within the same task. This study investigates the ability of two patients with left frontal tumours (KI: high grade glioma; PM: meningioma) to use a strategy to overcome profound suppression failures on the Hayling Test. KI and PM completed the Hayling Test and two experimental tasks. The Selection Investigation assessed verbal initiation on a sentence completion task that varied selection demands (high/low). The Suppression and Strategy Investigation assessed ability to implement four strategies aimed to override a suppression failure and facilitate production of an unconnected word. On the Hayling Test, KI and PM initiated responses to complete high constraint sentences, in contrast to impaired suppression. KI benefitted minimally from strategies to overcome suppression failure although one strategy (object naming) was partially successful. KI's errors revealed fast suppression errors, in contrast to slow no responses, and selection ability was also impaired for verbal initiation. PM, however, implemented each strategy 100% to overcome a suppression failure and had no difficulty completing sentences meaningfully, regardless of selection demands. This first investigation of strategy implementation to overcome profound suppression impairments provides insights into verbal initiation, inhibition, selection and strategy mechanisms, which has implications for neurorehabilitation. Specifically, both patients had profound inhibition deficits but KI also presented with a selection deficit and was unable to implement a strategy. By contrast, PM's selection ability was intact but she was unable to generate, rather than implement, a

Sublytic complement protects prostate cancer cells from tumour necrosis factor-α-induced cell death.

PubMed

Liu, L; Li, W; Li, Z; Kirschfink, M

2012-08-01

Inflammation is a critical component of tumour progression. Although complement and tumour necrosis factor (TNF)-α potentially exert significant anti-tumour effects, both mediators may also promote tumour progression. It has been demonstrated that sublytic complement confers resistance on tumour cells not only against lytic complement, but also other danger molecules such as perforin. In low concentrations, TNF promotes survival of malignant cells rather than exerting cytotoxic activity. In this study, we tested if sublytic complement is able to interfere with TNF-mediated tumour cell killing. Our results demonstrate that either subcytotoxic concentrations of TNF or sublytic complement rescue prostate carcinoma cells (DU145) from TNF-α-mediated cell death. Upon pretreatment with low-dose TNF-α, but not upon pre-exposure to sublytic complement, TNF resistance was associated with the down-regulation of TNF receptor 1 (TNF-R1) expression. Complement-induced protection against TNF-mediated apoptosis accompanied the induction of anti-apoptotic proteins [B cell leukaemia/lymphoma (Bcl)-2 and Bcl-xL] at an early stage followed by inhibition of the TNF-induced decrease in the amount of Bcl-2 and Bcl-xL. Cell protection also accompanied the inhibition of caspase-8 activation, poly (ADP-ribose) polymerase (PARP)-1 cleavage and the activation of nuclear factor (NF)-κB. Our data extend our current view on the induction of tumour cell resistance against cytotoxic mediators supporting the role of the tumour microenvironment in mediating protection against the anti-cancer immune response. © 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.

Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function.

PubMed

Storm, Elaine E; Durinck, Steffen; de Sousa e Melo, Felipe; Tremayne, Jarrod; Kljavin, Noelyn; Tan, Christine; Ye, Xiaofen; Chiu, Cecilia; Pham, Thinh; Hongo, Jo-Anne; Bainbridge, Travis; Firestein, Ron; Blackwood, Elizabeth; Metcalfe, Ciara; Stawiski, Eric W; Yauch, Robert L; Wu, Yan; de Sauvage, Frederic J

2016-01-07

Colorectal cancer remains a major unmet medical need, prompting large-scale genomics efforts in the field to identify molecular drivers for which targeted therapies might be developed. We previously reported the identification of recurrent translocations in R-spondin genes present in a subset of colorectal tumours. Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion-positive human tumour xenografts inhibits tumour growth and promotes differentiation. Notably, genes expressed in the stem-cell compartment of the intestine were among those most sensitive to anti-RSPO3 treatment. This observation, combined with functional assays, suggests that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumour growth and indicates that the therapeutic targeting of stem-cell properties within tumours may be a clinically relevant approach for the treatment of colorectal tumours.

SU-F-T-659: Nanoparticle-Aided Eye Plaque Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chin, J; Ngwa, W

Purpose: Eye plaque brachytherapy is one of the approaches for radiotherapy treatment for ocular cancers: retinoblastoma and choroidal melanoma. This study, investigates the potential benefits of using gold nanoparticles to enhance therapeutic efficacy during eye plaque brachytherapy. Methods: The EYE PHYSICS Inc. Plaque Simulator program distributed by IsoAid, LLC, Port Richey, Florida was used. It is based on the superposition of dose contributions from individual seeds following the TG–43 formalism. Dose enhancement factor (DEF) values for feasible nanoparticle concentrations from previous studies was used to investigate the benefit of using nanoparticles to enhance dose to tumour or reduce dose tomore » healthy tissue. The dose enhancement factor (DEF) represents the ratio of the dose deposited in tumour with nanoparticles divided by dose deposited in the tumour without nanoparticles. The investigation was done for I–125 and Pd–103 typical sources employed for eye plaque brachytherapy. The prescription dose used is 85 Gy. Results: Lower dose enhancement values were obtained for Pd–103. With DEF of 2 due to gold nanoparticles, critical structure doses reduce by a factor of 2. Optic disc dose is 6.69 Gy and 4.571 Gy, opposite retina dose is 4.064 and 2.484 Gy, lens dose is 12.66 Gy and 9.870 Gy, and fovea dose is 9.85 Gy and 7.275 Gy. With DEF of 3 due to gold nanoparticles, critical structure doses reduce by a factor of 3. Optic disc dose is 4.352 Gy and 2.975 Gy, opposite retina dose is 2.644 Gy and 1.618 Gy, lens dose is 8.322 Gy and 6.427 Gy, and fovea dose is 4.815 Gy and 4.737 Gy. Conclusion: The results of this research predict that using gold nanoparticles will lead to major sparing of dose to critical structures. The finding provides more impetus for the development of nanoparticle–aided brachytherapy.« less

Magnetic nanoparticle hyperthermia enhances radiation therapy: A study in mouse models of human prostate cancer

PubMed Central

Attaluri, Anilchandra; Kandala, Sri Kamal; Wabler, Michele; Zhou, Haoming; Cornejo, Christine; Armour, Michael; Hedayati, Mohammad; Zhang, Yonggang; DeWeese, Theodore L.; Herman, Cila; Ivkov, Robert

2015-01-01

Purpose We aimed to characterise magnetic nanoparticle hyperthermia (mNPH) with radiation therapy (RT) for prostate cancer. Methods Human prostate cancer subcutaneous tumours, PC3 and LAPC-4, were grown in nude male mice. When tumours measured 150 mm3 magnetic iron oxide nanoparticles (MIONPs) were injected into tumours to a target dose of 5.5 mg Fe/cm3 tumour, and treated 24 h later by exposure to alternating magnetic field (AMF). Mice were randomly assigned to one of four cohorts to characterise (1) intratumour MIONP distribution, (2) effects of variable thermal dose mNPH (fixed AMF peak amplitude 24 kA/m at 160±5 kHz) with/without RT (5 Gy), (3) effects of RT (RT5: 5 Gy; RT8: 8 Gy), and (4) fixed thermal dose mNPH (43 °C for 20min) with/without RT (5 Gy). MIONP concentration and distribution were assessed following sacrifice and tissue harvest using inductively coupled plasma mass spectrometry (ICP-MS) and Prussian blue staining, respectively. Tumour growth was monitored and compared among treated groups. Results LAPC-4 tumours retained higher MIONP concentration and more uniform distribution than did PC3 tumours. AMF power modulation provided similar thermal dose for mNPH and combination therapy groups (CEM43: LAPC-4: 33.6 ± 3.4 versus 25.9 ± 0.8, and PC3: 27.19 ± 0.7 versus 27.50 ± 0.6), thereby overcoming limitations of MIONP distribution and yielding statistically significant tumour growth delay. Conclusion PC3 and LAPC-4 tumours represent two biological models that demonstrate different patterns of nanoparticle retention and distribution, offering a model to make comparisons of these effects for mNPH. Modulating power for mNPH offers potential to overcome limitations of MIONP distribution to enhance mNPH. PMID:25811736

FAK-heterozygous mice display enhanced tumour angiogenesis.

PubMed

Kostourou, Vassiliki; Lechertier, Tanguy; Reynolds, Louise E; Lees, Delphine M; Baker, Marianne; Jones, Dylan T; Tavora, Bernardo; Ramjaun, Antoine R; Birdsey, Graeme M; Robinson, Stephen D; Parsons, Maddy; Randi, Anna M; Hart, Ian R; Hodivala-Dilke, Kairbaan

2013-01-01

Genetic ablation of endothelial focal adhesion kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularization. Here we show that reduced stromal FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumour growth in vivo. Our results highlight a potential novel role for FAK as a nonlinear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis.

Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents.

PubMed

Sagnella, Sharon M; Gong, Xiaojuan; Moghaddam, Minoo J; Conn, Charlotte E; Kimpton, Kathleen; Waddington, Lynne J; Krodkiewska, Irena; Drummond, Calum J

2011-03-01

We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipid prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.

Green synthesis of gold and silver nanoparticles from Cannabis sativa (industrial hemp) and their capacity for biofilm inhibition

PubMed Central

Singh, Priyanka; Pandit, Santosh; Garnæs, Jørgen; Tunjic, Sanja; Mokkapati, Venkata RSS; Sultan, Abida; Thygesen, Anders; Mackevica, Aiga; Mateiu, Ramona Valentina; Daugaard, Anders Egede; Baun, Anders; Mijakovic, Ivan

2018-01-01

Background Cannabis sativa (hemp) is a source of various biologically active compounds, for instance, cannabinoids, terpenes and phenolic compounds, which exhibit antibacterial, antifungal, anti-inflammatory and anticancer properties. With the purpose of expanding the auxiliary application of C. sativa in the field of bio-nanotechnology, we explored the plant for green and efficient synthesis of gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs). Methods and results The nanoparticles were synthesized by utilizing an aqueous extract of C. sativa stem separated into two different fractions (cortex and core [xylem part]) without any additional reducing, stabilizing and capping agents. In the synthesis of AuNPs using the cortex enriched in bast fibers, fiber-AuNPs (F-AuNPs) were achieved. When using the core part of the stem, which is enriched with phenolic compounds such as alkaloids and cannabinoids, core-AuNPs (C-AuNPs) and core-AgNPs (C-AgNPs) were formed. Synthesized nanoparticles were character-ized by UV–visible analysis, transmission electron microscopy, atomic force microscopy, dynamic light scattering, Fourier transform infrared, and matrix-assisted laser desorption/ionization time-of-flight. In addition, the stable nature of nanoparticles has been shown by thermogravimetric analysis and inductively coupled plasma mass spectrometry (ICP-MS). Finally, the AgNPs were explored for the inhibition of Pseudomonas aeruginosa and Escherichia coli biofilms. Conclusion The synthesized nanoparticles were crystalline with an average diameter between 12 and 18 nm for F-AuNPs and C-AuNPs and in the range of 20–40 nm for C-AgNPs. ICP-MS analysis revealed concentrations of synthesized nanoparticles as 0.7, 4.5 and 3.6 mg/mL for F-AuNPs, C-AuNPs and C-AgNPs, respectively. Fourier transform infrared spectroscopy revealed the presence of flavonoids, cannabinoids, terpenes and phenols on the nanoparticle surface, which could be responsible for reducing the salts to

Farnesylthiosalicylic acid-loaded lipid-polyethylene glycol-polymer hybrid nanoparticles for treatment of glioblastoma.

PubMed

Kaffashi, Abbas; Lüle, Sevda; Bozdağ Pehlivan, Sibel; Sarısözen, Can; Vural, İmran; Koşucu, Hüsnü; Demir, Taner; Buğdaycı, Kadir Emre; Söylemezoğlu, Figen; Karlı Oğuz, Kader; Mut, Melike

2017-08-01

We aimed to develop lipid-polyethylene glycol (PEG)-polymer hybrid nanoparticles, which have high affinity to tumour tissue with active ingredient, a new generation antineoplastic drug, farnesylthiosalicylic acid (FTA) for treatment of glioblastoma. Farnesylthiosalicylic acid-loaded poly(lactic-co-glycolic acid)-1,2 distearoyl-glycerol-3-phospho-ethanolamine-N [methoxy (PEG)-2000] ammonium salt (PLGA-DSPE-PEG) with or without 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) hybrid nanoparticles has been prepared and evaluated for in-vitro characterization. Cytotoxicity of FTA-loaded nanoparticles along with its efficacy on rat glioma-2 (RG2) cells was also evaluated both in vitro (in comparison with non-malignant cell line, L929) and in vivo. Scanning electron microscopy studies showed that all formulations prepared had smooth surface and spherical in shape. FTA and FTA-loaded nanoparticles have cytotoxic activity against RG2 glioma cell lines in cell culture studies, which further increases with addition of DOTAP. Magnetic resonance imaging and histopathologic evaluation on RG2 tumour cells in rat glioma model (49 female Wistar rats, 250-300 g) comparing intravenous and intratumoral injections of the drug have been performed and FTA-loaded nanoparticles reduced tumour size significantly in in-vivo studies, with higher efficiency of intratumoral administration than intravenous route. Farnesylthiosalicylic acid-loaded PLGA-DSPE-PEG-DOTAP hybrid nanoparticles are proven to be effective against glioblastoma in both in-vitro and in-vivo experiments. © 2017 Royal Pharmaceutical Society.

In vivo demonstration of enhanced radiotherapy using rare earth doped titania nanoparticles.

PubMed

Townley, Helen E; Kim, Jeewon; Dobson, Peter J

2012-08-21

Radiation therapy is often limited by damage to healthy tissue and associated side-effects; restricting radiation to ineffective doses. Preferential incorporation of materials into tumour tissue can enhance the effect of radiation. Titania has precedent for use in photodynamic therapy (PDT), generating reactive oxygen species (ROS) upon photoexcitation, but is limited by the penetration depth of UV light. Optimization of a nanomaterial for interaction with X-rays could be used for deep tumour treatment. As such, titania nanoparticles were doped with gadolinium to optimize the localized energy absorption from a conventional medical X-ray, and further optimized by the addition of other rare earth (RE) elements. These elements were selected due to their large X-ray photon interaction cross-section, and potential for integration into the titania crystal structure. Specific activation of the nanoparticles by X-ray can result in generation of ROS leading to cell death in a tumour-localized manner. We show here that intratumoural injection of RE doped titania nanoparticles can enhance the efficacy of radiotherapy in vivo.

Genetically engineered mesenchymal stromal cells producing TNFα have tumour suppressing effect on human melanoma xenograft.

PubMed

Tyciakova, Silvia; Matuskova, Miroslava; Bohovic, Roman; Polakova, Katarina; Toro, Lenka; Skolekova, Svetlana; Kucerova, Lucia

2015-01-01

Mesenchymal stromal cells (MSC) are a promising tool for targeted cancer therapy due to their tumour-homing ability. Intrinsic resistance enables the MSC to longer tolerate therapeutic factors, such as prodrug converting enzymes, cytokines and pro-apoptotic proteins. Tumour necrosis factor alpha (TNFα) is known to be cytotoxic to a variety of cancer cells and exert a tumour-destructive capacity. MSC were retrovirally transduced to stable express an exogenous gene encoding the desired therapeutic agent hTNFα. The effect of a TNFα-producing adipose tissue-derived MSC (AT-MSC/hTNFα) was tested on the tumour cell lines of different origins: melanoma (A375), breast carcinoma (SKBR3, MDA-MB-231), colon carcinoma (HT29), ovarian carcinoma (SKOV3) and glioblastoma (U87-MG) cells. The tumour suppressing effect of AT-MSC/hTNFα on A375 melanoma xenografts was monitored in an immunodeficient mouse model in vivo. Engineered AT-MSC are able to constitutively secrete human TNFα protein, induce apoptosis of tumour cell lines via caspase 3/7 activation and inhibit the tumour cell proliferation in vitro. Melanoma A375 and breast carcinoma SKBR3 cells were the most sensitive, and their proliferation in vitro was reduced by conditioned media produced by AT-MSC/hTNFα to 60% and 40%, respectively. The previously reported tumour supportive effect of AT-MSC on subcutaneous A375 melanoma xenograft growth was neutralised and suppressed by engineered AT-MSC stably producing hTNFα. When AT-MSC/hTNFα were coinjected with A375 melanoma cells, the tumour mass inhibition was up to 97.5%. The results of the present study demonstrate that tumour cells respond to hTNFα-based treatment mediated by genetically engineered AT-MSC/hTNFα both in vitro and in vivo. Copyright © 2015 John Wiley & Sons, Ltd.

Applications of Bacterial Magnetic Nanoparticles in Nanobiotechnology.

PubMed

Chen, Chuanfang; Wang, Pingping; Li, Linlin

2016-03-01

The bacterial magnetic nanoparticle (BMP) has been well researched in nanobiotechnology as a new magnetic crystal. The BMPs are extracted from magnetotactic bacteria and under precise biological control. Compared with engineered magnetic nanoparticles synthesized by chemical approaches, BMPs have the properties of large production, monodispersity, high crystallinity, and close-to-bulk magnetization, which enable BMPs to be the highly promising magnetic nanoparticles for nanobiotechnology. In this paper, we review the biomedical applications of BMPs in magnetic hyperthermia, drug treatment with tumour and bioseparation. In addition, the biodistribution and toxicity are also reviewed.

Hyperthermia using nanoparticles--Promises and pitfalls.

PubMed

Kaur, Punit; Aliru, Maureen L; Chadha, Awalpreet S; Asea, Alexzander; Krishnan, Sunil

2016-01-01

An ever-increasing body of literature affirms the physical and biological basis for sensitisation of tumours to conventional therapies such as chemotherapy and radiation therapy by mild temperature hyperthermia. This knowledge has fuelled the efforts to attain, maintain, measure and monitor temperature via technological advances. A relatively new entrant in the field of hyperthermia is nanotechnology which capitalises on locally injected or systemically administered nanoparticles that are activated by extrinsic energy sources to generate heat. This review describes the kinds of nanoparticles available for hyperthermia generation, their activation sources, their characteristics, and the unique opportunities and challenges with nanoparticle-mediated hyperthermia.

Zinc oxide nanoparticle suspensions and layer-by-layer coatings inhibit staphylococcal growth.

PubMed

McGuffie, Matthew J; Hong, Jin; Bahng, Joong Hwan; Glynos, Emmanouil; Green, Peter F; Kotov, Nicholas A; Younger, John G; VanEpps, J Scott

2016-01-01

Despite a decade of engineering and process improvements, bacterial infection remains the primary threat to implanted medical devices. Zinc oxide nanoparticles (ZnO-NPs) have demonstrated antimicrobial properties. Their microbial selectivity, stability, ease of production, and low cost make them attractive alternatives to silver NPs or antimicrobial peptides. Here we sought to (1) determine the relative efficacy of ZnO-NPs on planktonic growth of medically relevant pathogens; (2) establish the role of bacterial surface chemistry on ZnO-NP effectiveness; (3) evaluate NP shape as a factor in the dose-response; and (4) evaluate layer-by-layer (LBL) ZnO-NP surface coatings on biofilm growth. ZnO-NPs inhibited bacterial growth in a shape-dependent manner not previously seen or predicted. Pyramid shaped particles were the most effective and contrary to previous work, larger particles were more effective than smaller particles. Differential susceptibility of pathogens may be related to their surface hydrophobicity. LBL ZnO-NO coatings reduced staphylococcal biofilm burden by >95%. From the Clinical Editor: The use of medical implants is widespread. However, bacterial colonization remains a major concern. In this article, the authors investigated the use of zinc oxide nanoparticles (ZnO-NPs) to prevent bacterial infection. They showed in their experiments that ZnO-NPs significantly inhibited bacterial growth. This work may present a new alternative in using ZnO-NPs in medical devices. Copyright © 2015 Elsevier Inc. All rights reserved.

VEGF(121)b, a new member of the VEGF(xxx)b family of VEGF-A splice isoforms, inhibits neovascularisation and tumour growth in vivo.

PubMed

Rennel, E S; Varey, A H R; Churchill, A J; Wheatley, E R; Stewart, L; Mather, S; Bates, D O; Harper, S J

2009-10-06

The key mediator of new vessel formation in cancer and other diseases is VEGF-A. VEGF-A exists as alternatively spliced isoforms - the pro-angiogenic VEGF(xxx) family generated by exon 8 proximal splicing, and a sister family, termed VEGF(xxx)b, exemplified by VEGF(165)b, generated by distal splicing of exon 8. However, it is unknown whether this anti-angiogenic property of VEGF(165)b is a general property of the VEGF(xxx)b family of isoforms. The mRNA and protein expression of VEGF(121)b was studied in human tissue. The effect of VEGF(121)b was analysed by saturation binding to VEGF receptors, endothelial migration, apoptosis, xenograft tumour growth, pre-retinal neovascularisation and imaging of biodistribution in tumour-bearing mice with radioactive VEGF(121)b. The existence of VEGF(121)b was confirmed in normal human tissues. VEGF(121)b binds both VEGF receptors with similar affinity as other VEGF isoforms, but inhibits endothelial cell migration and is cytoprotective to endothelial cells through VEGFR-2 activation. Administration of VEGF(121)b normalised retinal vasculature by reducing both angiogenesis and ischaemia. VEGF(121)b reduced the growth of xenografted human colon tumours in association with reduced microvascular density, and an intravenous bolus of VEGF(121)b is taken up into colon tumour xenografts. Here we identify a second member of the family, VEGF(121)b, with similar properties to those of VEGF(165)b, and underline the importance of the six amino acids of exon 8b in the anti-angiogenic activity of the VEGF(xxx)b isoforms.

Can hi-jacking hypoxia inhibit extracellular vesicles in cancer?

PubMed

Lowry, Michelle C; O'Driscoll, Lorraine

2018-06-01

Increasing evidence indicates that extracellular vesicles (EVs) are key players in undesirable cell-cell communication in cancer. However, the release of EVs is not unique to cancer cells; normal cells release EVs to perform physiological roles. Thus, selective inhibition of EV release from cancer cells is desirable. Hypoxia contributes to tumour development and aggressiveness. EV quantities and thus undesirable communications are substantially increased in hypoxia. Targeting hypoxia could selectively inhibit EV release from tumour cells without disturbing physiologically relevant EVs. The unfavourable association between hypoxia and EV release is evident in multiple tumour types; therefore, targeting hypoxia could have a broad therapeutic benefit. Copyright © 2018 Elsevier Ltd. All rights reserved.

Retro-inverso d-peptide-modified hyaluronic acid/bioreducible hyperbranched poly(amido amine)/pDNA core-shell ternary nanoparticles for the dual-targeted delivery of short hairpin RNA-encoding plasmids.

PubMed

Gu, Jijin; Chen, Xinyi; Fang, Xiaoling; Sha, Xianyi

2017-07-15

The active targeting of gene carriers is a powerful strategy for improving tumour-specific delivery and therapy. Although numerous l-peptide ligands play significant roles in the active targeting of nanomedicine, retro-inverso d-peptides have been explored as targeting ligands due to their superior stability and bioactivity in vivo. In this study, retro-inverso d-peptide (RIF7)-modified hyaluronic acid (HA)/bioreducible hyperbranched poly(amido amine) (RHB)/plasmid DNA (pDNA) ternary nanoparticles were successfully developed using the layer-by-layer method for the CD44-positive tumour-specific delivery of short hairpin RNA (shRNA)-encoding pDNA through the combination of the Anxa1 (tumour vasculature) and CD44 (tumour cell-surface) receptors, which mediated the dual targeting. The potential of these newly designed nanoparticles was evaluated by examining the efficacy of their cellular uptake and transfection in cell monolayers, tumour spheroids, and malignant xenograft animal models. With negligible cytotoxicity, the spherical-shaped RIF7-HA/RHB/pDNA nanoparticles were the direct result of an electrostatic complex that had efficiently targeted CD44-positive tumour delivery, penetration, and cellular uptake in vitro. The nanoparticles showed excellent target-specific gene transfection even in the presence of serum. The in vivo therapeutic effect of RIF7-HA/RHB/pDNA-shRNA nanoparticle-mediated shRNA targeting of the Cyclin gene (shCyclin) was evaluated in tumour-bearing mice. The RIF7-HA/RHB/pDNA-shCyclin nanoparticles significantly increased the survival time of tumour-bearing mice and substantially reduced tumour growth due to their extremely specific tumour-targeting activity. These results suggested that the combination of HA and retro-inverso peptide RIF7 significantly increased the therapeutic effect of pDNA-shCyclin-loaded nanoparticles for CD44-positive tumours. Thus, RIF7-HA-mediated multi-target ternary gene vectors are an efficient and promising strategy

The germacranolide sesquiterpene lactone neurolenin B of the medicinal plant Neurolaena lobata (L.) R.Br. ex Cass inhibits NPM/ALK-driven cell expansion and NF-κB-driven tumour intravasation.

PubMed

Unger, Christine; Kiss, Izabella; Vasas, Andrea; Lajter, Ildikó; Kramer, Nina; Atanasov, Atanas Georgiev; Nguyen, Chi Huu; Chatuphonprasert, Waranya; Brenner, Stefan; Krieger, Sigurd; McKinnon, Ruxandra; Peschel, Andrea; Kain, Renate; Saiko, Philipp; Szekeres, Thomas; Kenner, Lukas; Hassler, Melanie R; Diaz, Rene; Frisch, Richard; Dirsch, Verena M; Jäger, Walter; de Martin, Rainer; Bochkov, Valery N; Passreiter, Claus M; Peter-Vörösmarty, Barbara; Mader, Robert M; Grusch, Michael; Dolznig, Helmut; Kopp, Brigitte; Zupko, Istvan; Hohmann, Judit; Krupitza, Georg

2015-08-15

The t(2;5)(p23;q35) chromosomal translocation results in the expression of the fusion protein NPM/ALK that when expressed in T-lymphocytes gives rise to anaplastic large cell lymphomas (ALCL). In search of new therapy options the dichloromethane extract of the ethnomedicinal plant Neurolaena lobata (L.) R.Br. ex Cass was shown to inhibit NPM/ALK expression. Therefore, we analysed whether the active principles that were recently isolated and found to inhibit inflammatory responses specifically inhibit growth of NPM/ALK+ ALCL, leukaemia and breast cancer cells, but not of normal cells, and the intravasation through the lymphendothelial barrier. ALCL, leukaemia and breast cancer cells, and normal peripheral blood mononuclear cells (PBMCs) were treated with isolated sesquiterpene lactones and analysed for cell cycle progression, proliferation, mitochondrial activity, apoptosis, protein and mRNA expression, NF-κB and cytochrome P450 activity, 12(S)-HETE production and lymphendothelial intravasation. In vitro treatment of ALCL by neurolenin B suppressed NPM/ALK, JunB and PDGF-Rβ expression, inhibited the growth of ALCL cells late in M phase, and induced apoptosis via caspase 3 without compromising mitochondrial activity (as a measure of general exogenic toxicity). Moreover, neurolenin B attenuated tumour spheroid intravasation probably through inhibition of NF-κB and CYP1A1. Neurolenin B specifically decreased pro-carcinogenic NPM/ALK expression in ALK+ ALCL cells and, via the inhibition of NF-kB signalling, attenuated tumour intra/extravasation into the lymphatics. Hence, neurolenin B may open new options to treat ALCL and to manage early metastatic processes to which no other therapies exist. Copyright © 2015 Elsevier GmbH. All rights reserved.

Dairy milk fat augments paclitaxel therapy to suppress tumour metastasis in mice, and protects against the side-effects of chemotherapy.

PubMed

Sun, Xueying; Zhang, Jie; Gupta, Rita; Macgibbon, Alastair K H; Kuhn-Sherlock, Barbara; Krissansen, Geoffrey W

2011-10-01

Milk fat is a natural product containing essential nutrients as well as fatty acids and other food factors with reported anti-cancer potential. Here bovine milk fat was tested for its ability to inhibit the growth of breast and colon cancers and their metastasis to the lung and liver; either alone or in combination with the chemotherapeutic agent paclitaxel. A diet containing 5% typical anhydrous milk fat (representing ~70% of the total dietary fat component) fed to Balb/c mice delayed the appearance of subcutaneous 4T1 breast and CT26 colon cancer tumours and inhibited their metastasis to the lung and liver, when compared to the control diet containing soybean oil as the only fat component. It augmented the inhibitory effects of paclitaxel on tumour growth and metastasis, and reduced the microvessel density of tumours. It displayed no apparent organ toxicity, but instead was beneficial for well-being of tumour-bearing mice by maintaining gastrocnemius muscle and epididymal adipose tissue that were otherwise depleted by cachexia. The milk fat diet ameliorated gut damage caused by paclitaxel in non-tumour-bearing mice, as evidenced by retention of jejunal morphology, villi length and intestinal γ-glutamyl transpeptidase activity, and inhibition of crypt apoptosis. It prevented loss of red and white blood cells due to both cancer-mediated immunosuppression and the cytotoxic effects of chemotherapy. The present study warrants the use of milk fat as an adjuvant to inhibit tumour metastasis during cancer chemotherapy, and to spare patients from the debilitating side-effects of cytotoxic drugs.

Anti-metastatic effects of viral and non-viral mediated Nk4 delivery to tumours.

PubMed

Buhles, Alexandra; Collins, Sara A; van Pijkeren, Jan P; Rajendran, Simon; Miles, Michelle; O'Sullivan, Gerald C; O'Hanlon, Deirdre M; Tangney, Mark

2009-03-09

The most common cause of death of cancer sufferers is through the occurrence of metastases. The metastatic behaviour of tumour cells is regulated by extracellular growth factors such as hepatocyte growth factor (HGF), a ligand for the c-Met receptor tyrosine kinase, and aberrant expression/activation of the c-Met receptor is closely associated with metastatic progression. Nk4 (also known as Interleukin (IL)32b) is a competitive antagonist of the HGF c-Met system and inhibits c-Met signalling and tumour metastasis. Nk4 has an additional anti-angiogenic activity independent of its HGF-antagonist function. Angiogenesis-inhibitory as well as cancer-specific apoptosis inducing effects make the Nk4 sequence an attractive candidate for gene therapy of cancer. This study investigates the inhibition of tumour metastasis by gene therapy mediated production of Nk4 by the primary tumour. Optimal delivery of anti-cancer genes is vital in order to achieve the highest therapeutic responses. Non-viral plasmid delivery methods have the advantage of safety and ease of production, providing immediate transgene expression, albeit short-lived in most tumours. Sustained presence of anti-angiogenic molecules is preferable with anti-angiogenic therapies, and the long-term expression mediated by Adeno-associated Virus (AAV) might represent a more appropriate delivery in this respect. However, the incubation time required by AAV vectors to reach appropriate gene expression levels hampers efficacy in many fast-growing murine tumour models. Here, we describe murine trials assessing the effects of Nk4 on the spontaneously metastatic Lewis Lung Carcinoma (LLC) model when delivered to primary tumour via plasmid lipofection or AAV2 vector. Intratumoural AAV-Nk4 administration produced the highest therapeutic response with significant reduction in both primary tumour growth and incidence of lung metastases. Plasmid-mediated therapy also significantly reduced metastatic growth, but with moderate

Nanostructured nanoparticles of self-assembled lipid pro-drugs as a route to improved chemotherapeutic agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sagnella, Sharon M.; Gong, Xiaojuan; Moghaddam, Minoo J.

2014-09-24

We demonstrate that oral delivery of self-assembled nanostructured nanoparticles consisting of 5-fluorouracil (5-FU) lipid prodrugs results in a highly effective, target-activated, chemotherapeutic agent, and offers significantly enhanced efficacy over a commercially available alternative that does not self-assemble. The lipid prodrug nanoparticles have been found to significantly slow the growth of a highly aggressive mouse 4T1 breast tumour, and essentially halt the growth of a human MDA-MB-231 breast tumour in mouse xenografts. Systemic toxicity is avoided as prodrug activation requires a three-step, enzymatic conversion to 5-FU, with the third step occurring preferentially at the tumour site. Additionally, differences in the lipidmore » prodrug chemical structure and internal nanostructure of the nanoparticle dictate the enzymatic conversion rate and can be used to control sustained release profiles. Thus, we have developed novel oral nanomedicines that combine sustained release properties with target-selective activation.« less

Coupled modelling of tumour angiogenesis, tumour growth and blood perfusion.

PubMed

Cai, Yan; Xu, Shixiong; Wu, Jie; Long, Quan

2011-06-21

We propose a mathematical modelling system to investigate the dynamic process of tumour cell proliferation, death and tumour angiogenesis by fully coupling the vessel growth, tumour growth and blood perfusion. Tumour growth and angiogenesis are coupled by the chemical microenvironment and the cell-matrix interaction. The haemodynamic calculation is carried out on the updated vasculature. The domains of intravascular, transcapillary and interstitial fluid flow were coupled in the model to provide a comprehensive solution of blood perfusion variables. An estimation of vessel collapse is made according to the wall shear stress criterion to provide feedback on vasculature remodelling. The simulation can show the process of tumour angiogenesis and the spatial distribution of tumour cells for periods of up to 24 days. It can show the major features of tumour and tumour microvasculature during the period such as the formation of a large necrotic core in the tumour centre with few functional vessels passing through, and a well circulated tumour periphery regions in which the microvascular density is high and associated with more aggressive proliferating cells of the growing tumour which are all consistent with physiological observations. The study also demonstrated that the simulation results are not dependent on the initial tumour and networks, which further confirms the application of the coupled model feedback mechanisms. The model enables us to examine the interactions between angiogenesis and tumour growth, and to study the dynamic response of a solid tumour to the changes in the microenvironment. This simulation framework can be a foundation for further applications such as drug delivery and anti-angiogenic therapies. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

A monoclonal antibody against KCNK9 K(+) channel extracellular domain inhibits tumour growth and metastasis.

PubMed

Sun, Han; Luo, Liqun; Lal, Bachchu; Ma, Xinrong; Chen, Lieping; Hann, Christine L; Fulton, Amy M; Leahy, Daniel J; Laterra, John; Li, Min

2016-02-04

Two-pore domain potassium (K2P) channels act to maintain cell resting membrane potential--a prerequisite for many biological processes. KCNK9, a member of K2P family, is implicated in cancer, owing to its overexpression in human tumours and its ability to promote neoplastic cell survival and growth. However, KCNK9's underlying contributions to malignancy remain elusive due to the absence of specific modulators. Here we describe the development of monoclonal antibodies against the KCNK9 extracellular domain and their functional effects. We show that one antibody (Y4) with the highest affinity binding induces channel internalization. The addition of Y4 to KCNK9-expressing carcinoma cells reduces cell viability and increases cell death. Systemic administration of Y4 effectively inhibits growth of human lung cancer xenografts and murine breast cancer metastasis in mice. Evidence for Y4-mediated carcinoma cell autonomous and immune-dependent cytotoxicity is presented. Our study reveals that antibody-based KCNK9 targeting is a promising therapeutic strategy in KCNK9-expressing malignancies.

The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters.

PubMed

Nancolas, Bethany; Guo, Lili; Zhou, Rong; Nath, Kavindra; Nelson, David S; Leeper, Dennis B; Blair, Ian A; Glickson, Jerry D; Halestrap, Andrew P

2016-04-01

Lonidamine (LND) is an anti-tumour drug particularly effective at selectively sensitizing tumours to chemotherapy, hyperthermia and radiotherapy, although its precise mode of action remains unclear. It has been reported to perturb the bioenergetics of cells by inhibiting glycolysis and mitochondrial respiration, whereas indirect evidence suggests it may also inhibit L-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). In the present study, we test these possibilities directly. We demonstrate that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki2.5 μM) and co-operatively inhibits L-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevisoocytes with K0.5 and Hill coefficient values of 36-40 μM and 1.65-1.85 respectively. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC50~ 7 μM) than other substrates including glutamate (IC50~ 20 μM). In isolated DB-1 melanoma cells 1-10 μM LND increased L-lactate output, consistent with MPC inhibition, but higher concentrations (150 μM) decreased L-lactate output whereas increasing intracellular [L-lactate] > 5-fold, consistent with MCT inhibition. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated L-lactic acid efflux and glutamine/glutamate oxidation. Together these actions can account for published data on the selective tumour effects of LND onL-lactate, intracellular pH (pHi) and ATP levels that can be partially mimicked by the established MPC and MCT inhibitor α-cyano-4-hydroxycinnamate (CHC). © 2016 Authors; published by Portland Press Limited.

The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters

PubMed Central

Nancolas, Bethany; Guo, Lili; Zhou, Rong; Nath, Kavindra; Nelson, David S.; Leeper, Dennis B.; Blair, Ian A.; Glickson, Jerry D.; Halestrap, Andrew P.

2016-01-01

Lonidamine (LND) is an anti-tumour drug particularly effective at selectively sensitising tumours to chemotherapy, hyperthermia and radiotherapy, although its precise mode of action remains unclear. It has been reported to perturb the bioenergetics of cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggests it may also inhibit L-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). Here we test these possibilities directly. We demonstrate that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki 2.5 μM) and cooperatively inhibits L-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K0.5 and Hill Coefficient values of 36–40 μM and 1.65–1.85. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC50 ~7 μM) than other substrates including glutamate (IC50 ~20 μM). In isolated DB-1 melanoma cells 1–10 μM LND increased L-lactate output, consistent with MPC inhibition, but higher concentrations (150 μM) decreased L-lactate output while increasing intracellular [L-lactate] > five-fold, consistent with MCT inhibition. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated L-lactic acid efflux and glutamine/glutamate oxidation. Together these actions can account for published data on the selective tumour effects of LND on L-lactate, intracellular pH (pHi) and ATP levels that can be partially mimicked by the established MPC and MCT inhibitor α-cyano-4-hydroxycinnamate. PMID:26831515

Candida tropicalis biofilm inhibition by ZnO nanoparticles and EDTA.

PubMed

Jothiprakasam, Vinoth; Sambantham, Murugan; Chinnathambi, Stalin; Vijayaboopathi, Singaravel

2017-01-01

Biofilm of Candida tropicalis denote as a complex cellular congregation with major implication in pathogenesis. This lifestyle of fungus as a biofilm can inhibit immune system and antifungal therapy in treatment of infectious disease especially medical device associated chronic disease. In this study effects of Zinc Oxide (ZnO) nanoparticles and EDTA were evaluated on C. tropicalis biofilm by using different techniques. ZnO nanoparticles were synthesized from Egg albumin. To assay the formation of biofilm of yeast cells like Fluconazole-susceptible C. tropicalis (ATCC 13,803) and fluconazole-resistant standard strains of C. tropicalis (ATCC 750) were grown in 24 well plates and antifungal effect of ZnO and EDTA were evaluated on C. tropicalis biofilm using ATP bioluminescence and tetrasodium salt (XTT) reduction assays. Synthesized ZnO NPs and EDTA had effective antifungal properties at the concentration of 5.2, 8.6μg/ml for Fluconazole susceptible strain and 5.42, 10.8μg/ml Fluconazole resistant strains of C. tropicalis biofilms compared to fluconazole drug. In present study we conclude, ZnO considered as a new agent in field of prevention C. tropicalis biofilms especially biofilms formed surface of medical device. Copyright © 2016 Elsevier Ltd. All rights reserved.

Tumour location within the breast: Does tumour site have prognostic ability?

PubMed

Rummel, Seth; Hueman, Matthew T; Costantino, Nick; Shriver, Craig D; Ellsworth, Rachel E

2015-01-01

Tumour location within the breast varies with the highest frequency in the upper outer quadrant (UOQ) and lowest frequency in the lower inner quadrant (LIQ). Whether tumour location is prognostic is unclear. To determine whether tumour location is prognostic, associations between tumour site and clinicopathological characteristics were evaluated. All patients enrolled in the Clinical Breast Care Project whose tumour site-UOQ, upper inner quadrant (UIQ), central, LIQ, lower outer quadrant (LOQ)-was determined by a single, dedicated breast pathologist were included in this study. Patients with multicentric disease (n = 122) or tumours spanning multiple quadrants (n = 381) were excluded from further analysis. Clinicopathological characteristics were analysed using chi-square tests for univariate analysis with multivariate analysis performed using principal components analysis (PCA) and multiple logistic regression. Significance was defined as P < 0.05. Of the 980 patients with defined tumour location, 30 had bilateral disease. Tumour location in the UOQ (51.5%) was significantly higher than in the UIQ (15.6%), LOQ (14.2%), central (10.6%), or LIQ (8.1%). Tumours in the central quadrant were significantly more likely to have higher tumour stage (P = 0.003) and size (P < 0.001), metastatic lymph nodes (P < 0.001), and mortality (P = 0.011). After multivariate analysis, only tumour size and lymph node status remained significantly associated with survival. Evaluation of tumour location as a prognostic factor revealed that although tumours in the central region are associated with less favourable outcome, these associations are not independent of location but rather driven by larger tumour size. Tumours in the central region are more difficult to detect mammographically, resulting in larger tumour size at diagnosis and thus less favourable prognosis. Together, these data demonstrate that tumour location is not an independent prognostic factor.

Anti-tumour and immunomodulatory activities of oligosaccharides isolated from Panax ginseng C.A. Meyer.

PubMed

Jiao, Lili; Zhang, Xiaoyu; Li, Bo; Liu, Zhen; Wang, Mingzhu; Liu, Shuying

2014-04-01

Water-soluble ginseng oligosaccharides (WGOS) composed of D-glucose with a degree of polymerisation ranging from 2 to 14 were obtained from Panax ginseng C.A. Meyer. In this study, the anti-tumour and immunoregulatory effects of WGOS were evaluated in Hepatoma-22 (H22)-bearing mice. Treatment with WGOS inhibited tumour growth in vivo and significantly increased relative spleen and thymus weight, serum tumour necrosis factor-α level, spleen lymphocyte proliferation, natural killer cell activity, phagocytic function and nitric oxide production secreted by macrophage in H22-bearing mice. However, no direct cytotoxicity was detected. Therefore, the anti-tumour activity of WGOS may be related to their immunomodulatory effects. Copyright © 2014 Elsevier B.V. All rights reserved.

Oocyte exposure to ZnO nanoparticles inhibits early embryonic development through the γ-H2AX and NF-κB signaling pathways.

PubMed

Liu, Jing; Zhao, Yong; Ge, Wei; Zhang, Pengfei; Liu, Xinqi; Zhang, Weidong; Hao, Yanan; Yu, Shuai; Li, Lan; Chu, Meiqiang; Min, Lingjiang; Zhang, Hongfu; Shen, Wei

2017-06-27

The impacts of zinc oxide nanoparticles on embryonic development following oocyte stage exposure are unknown and the underlying mechanisms are sparsely understood. In the current investigation, intact nanoparticles were detected in ovarian tissue in vivo and cultured cells in vitro under zinc oxide nanoparticles treatment. Zinc oxide nanoparticles exposure during the oocyte stage inhibited embryonic development. Notably, in vitro culture data closely matched in vivo embryonic data, in that the impairments caused by Zinc oxide nanoparticles treatment passed through cell generations; and both gamma-H2AX and NF-kappaB pathways were involved in zinc oxide nanoparticles caused embryo-toxicity. Copper oxide and silicon dioxide nanoparticles have been used to confirm that particles are important for the toxicity of zinc oxide nanoparticles. The toxic effects of zinc oxide nanoparticles emanate from both intact nanoparticles and Zn2+. Our investigation along with others suggests that zinc oxide nanoparticles are toxic to the female reproductive system [ovaries (oocytes)] and subsequently embryo-toxic and that precaution should be taken regarding human exposure to their everyday use.

Oocyte exposure to ZnO nanoparticles inhibits early embryonic development through the γ-H2AX and NF-κB signaling pathways

PubMed Central

Liu, Jing; Zhao, Yong; Ge, Wei; Zhang, Pengfei; Liu, Xinqi; Zhang, Weidong; Hao, Yanan; Yu, Shuai; Li, Lan; Chu, Meiqiang; Min, Lingjiang; Zhang, Hongfu; Shen, Wei

2017-01-01

The impacts of zinc oxide nanoparticles on embryonic development following oocyte stage exposure are unknown and the underlying mechanisms are sparsely understood. In the current investigation, intact nanoparticles were detected in ovarian tissue in vivo and cultured cells in vitro under zinc oxide nanoparticles treatment. Zinc oxide nanoparticles exposure during the oocyte stage inhibited embryonic development. Notably, in vitro culture data closely matched in vivo embryonic data, in that the impairments caused by Zinc oxide nanoparticles treatment passed through cell generations; and both gamma-H2AX and NF-kappaB pathways were involved in zinc oxide nanoparticles caused embryo-toxicity. Copper oxide and silicon dioxide nanoparticles have been used to confirm that particles are important for the toxicity of zinc oxide nanoparticles. The toxic effects of zinc oxide nanoparticles emanate from both intact nanoparticles and Zn2+. Our investigation along with others suggests that zinc oxide nanoparticles are toxic to the female reproductive system [ovaries (oocytes)] and subsequently embryo-toxic and that precaution should be taken regarding human exposure to their everyday use. PMID:28487501

Sinonasal haemangiopericytoma-like tumour: a sinonasal glomus tumour or a haemangiopericytoma?

PubMed

Tse, L L Y; Chan, J K C

2002-06-01

Sinonasal haemangiopericytoma-like tumour is controversial with regard to its nosologic nature. This study aims to investigate its relationship with glomus tumour and haemangiopericytoma. Six cases of sinonasal haemangiopericytoma-like tumours identified in our files were reviewed for clinicopathological features, and compared with five cases each of soft tissue glomus tumour and meningeal haemangiopericytoma. Immunohistochemical studies for muscle-specific actin, smooth muscle actin, desmin and CD34 were performed. Sinonasal haemangiopericytoma-like tumour demonstrated a uniform histological appearance with bland-looking short, spindly cells forming sheets and short fascicles. The tumour cells were interspersed with slit-like, round and ectatic blood vessels. Actin immunoreactivity was demonstrated in all six cases, although occasionally patchy. The histological appearance and immunohistochemical phenotype of sinonasal haemangiopericytoma-like tumour were very similar to and focally indistinguishable from glomus tumour. Meningeal haemangiopericytoma, in contrast, was characterized by high tumour cellularity, random nuclear orientation, presence of staghorn vasculature and lack of immunohistochemical evidence of myogenic differentiation. We conclude that sinonasal haemangiopericytoma-like tumour is biologically close to or identical to glomus tumour, but is not related to haemangiopericytoma.

Decorin-loaded poly lactic-co-glycolic acid nanoparticles modified by anti-alpha fetoprotein antibody: preparation, proliferation inhibition and induced apoptosis effects on HepG2 cells in vitro.

PubMed

Yang, Qiaoli; Wang, Shuyue; Wang, Yuan; Qu, Yane; Xue, Jun; Mi, Yang; Wang, Yanhong; Luo, Xuguang; Deng, Zhihua; Wang, Guiqin

2017-06-01

Decorin (DCN) is a negative regulatory factor for the growth of cancer cells and can inhibit the proliferation, metastasis of cancer cells and angiogenesis in cancer tissues. The aims of this study were to prepare the nanoparticles consisting of DCN and poly lactic-co-glycolic acid (PLGA) modified by anti-alpha fetoprotein (AFP) monoclonal antibody (mAb) and to examine the conventional physical properties, the in-vitro release of DCN and the targeting effect of these nanoparticles on HepG2 cells. The encapsulated plasmid was slowly and steadily released from the nanoparticles. The targeted PLGA nanoparticles were initiatively taken in HepG2 cells high-efficiently. According to the results of RT-PCR, DCN gene in AFPmAb-PLGA-rhDCN nanoparticles can be expressed in HepG2 cells successfully. These nanoparticles significantly inhibited the proliferation of HepG2 cells and induced apoptosis. The mRNA expression of Bcl-2 gene in the AFPmAb-PLGA-rhDCN-treated groups appeared significantly to decrease and the caspase-3 gene had the opposite trend as compared with that of control group (P < 0.01). These studies revealed that these nanoparticles were capable of specifically targeting the HepG2 cells and inhibiting the proliferation and they induce apoptosis of HepG2 cells in vitro, which was in a dose- and time-dependent manner. © 2017 Royal Pharmaceutical Society.

Magnetic nanoparticle hyperthermia enhances radiation therapy: A study in mouse models of human prostate cancer.

PubMed

Attaluri, Anilchandra; Kandala, Sri Kamal; Wabler, Michele; Zhou, Haoming; Cornejo, Christine; Armour, Michael; Hedayati, Mohammad; Zhang, Yonggang; DeWeese, Theodore L; Herman, Cila; Ivkov, Robert

2015-06-01

We aimed to characterise magnetic nanoparticle hyperthermia (mNPH) with radiation therapy (RT) for prostate cancer. Human prostate cancer subcutaneous tumours, PC3 and LAPC-4, were grown in nude male mice. When tumours measured 150 mm3 magnetic iron oxide nanoparticles (MIONPs) were injected into tumours to a target dose of 5.5 mg Fe/cm3 tumour, and treated 24 h later by exposure to alternating magnetic field (AMF). Mice were randomly assigned to one of four cohorts to characterise (1) intratumour MIONP distribution, (2) effects of variable thermal dose mNPH (fixed AMF peak amplitude 24 kA/m at 160 ± 5 kHz) with/without RT (5 Gy), (3) effects of RT (RT5: 5 Gy; RT8: 8 Gy), and (4) fixed thermal dose mNPH (43 °C for 20 min) with/without RT (5 Gy). MIONP concentration and distribution were assessed following sacrifice and tissue harvest using inductively coupled plasma mass spectrometry (ICP-MS) and Prussian blue staining, respectively. Tumour growth was monitored and compared among treated groups. LAPC-4 tumours retained higher MIONP concentration and more uniform distribution than did PC3 tumours. AMF power modulation provided similar thermal dose for mNPH and combination therapy groups (CEM43: LAPC-4: 33.6 ± 3.4 versus 25.9 ± 0.8, and PC3: 27.19 ± 0.7 versus 27.50 ± 0.6), thereby overcoming limitations of MIONP distribution and yielding statistically significant tumour growth delay. PC3 and LAPC-4 tumours represent two biological models that demonstrate different patterns of nanoparticle retention and distribution, offering a model to make comparisons of these effects for mNPH. Modulating power for mNPH offers potential to overcome limitations of MIONP distribution to enhance mNPH.

Tumour cell dispersion by the ultrasonic aspirator during brain tumour resection.

PubMed

Preston, J K; Masciopinto, J; Salamat, M S; Badie, B

1999-10-01

Ultrasonic aspirators are commonly used to resect brain tumours because they allow safe, rapid and accurate removal of diseased tissue. Since ultrasonic aspirators generate a spray of aerosolized irrigating fluid around the instrument tip, we questioned whether this spray might contain viable tumours cells that could contribute to intraoperative spread of tumour fragments. To test this hypothesis, we collected the spray produced during the resection of nine brain tumours with an ultrasonic aspirator and semi-quantitatively analysed it for tumour presence. The aerosolized irrigation fluid was found to contain intact tumour cells or clumps of tumour cells in all nine instances, and there was a trend of increasing tumour cell dispersion with increasing ultrasonic aspiration times. Further examination is required to determine if this intraoperative dispersion of apparently viable tumour fragments contributes to local neoplasm recurrence.

Effect of Nanoparticles on Modified Screen Printed Inhibition Superoxide Dismutase Electrodes for Aluminum

PubMed Central

Barquero-Quirós, Miriam; Arcos-Martínez, María Julia

2016-01-01

A novel amperometric biosensor for the determination of Al(III) based on the inhibition of the enzyme superoxide dismutase has been developed. The oxidation signal of epinephrine substrate was affected by the presence of Al(III) ions leading to a decrease in its amperometric current. The immobilization of the enzyme was performed with glutaraldehyde on screen-printed carbon electrodes modifiedwith tetrathiofulvalene (TTF) and different types ofnanoparticles. Nanoparticles of gold, platinum, rhodium and palladium were deposited on screen printed carbon electrodes by means of two electrochemical procedures. Nanoparticles were characterized trough scanning electronic microscopy, X-rays fluorescence, and atomic force microscopy. Palladium nanoparticles showed lower atomic force microscopy parameters and higher slope of aluminum calibration curves and were selected to perform sensor validation. The developed biosensor has a detection limit of 2.0 ± 0.2 μM for Al(III), with a reproducibility of 7.9% (n = 5). Recovery of standard reference material spiked to buffer solution was 103.8% with a relative standard deviation of 4.8% (n = 5). Recovery of tap water spiked with the standard reference material was 100.5 with a relative standard deviation of 3.4% (n = 3). The study of interfering ions has also been carried out. PMID:27681735

Platelets Inhibit Migration of Canine Osteosarcoma Cells.

PubMed

Bulla, S C; Badial, P R; Silva, R C; Lunsford, K; Bulla, C

2017-01-01

The interaction between platelets and tumour cells is important for tumour growth and metastasis. Thrombocytopenia or antiplatelet treatment negatively impact on cancer metastasis, demonstrating potentially important roles for platelets in tumour progression. To our knowledge, there is no information regarding the role of platelets in cancer progression in dogs. This study was designed to test whether canine platelets affected the migratory behaviour of three canine osteosarcoma cell lines and to give insights of molecular mechanisms. Intact platelets, platelet lysate and platelet releasate inhibited the migration of canine osteosarcoma cell lines. Addition of blood leucocytes to the platelet samples did not alter the inhibitory effect on migration. Platelet treatment also significantly downregulated the transcriptional levels of SNAI2 and TWIST1 genes. The interaction between canine platelets or molecules released during platelet activation and these tumour cell lines inhibits their migration, which suggests that canine platelets might antagonize metastasis of canine osteosarcoma. This effect is probably due to, at least in part, downregulation of genes related to epithelial-mesenchymal transition. Copyright © 2016. Published by Elsevier Ltd.

Inhibition of HIV Fusion with Multivalent Gold Nanoparticles

PubMed Central

Bowman, Mary-Catherine; Ballard, T. Eric; Ackerson, Christopher J.; Feldheim, Daniel L.; Margolis, David M.; Melander, Christian

2010-01-01

The design and synthesis of a multivalent gold nanoparticle therapeutic is presented. SDC-1721, a fragment of the potent HIV inhibitor TAK-779, was synthesized and conjugated to 2.0 nm diameter gold nanoparticles. Free SDC-1721 had no inhibitory effect on HIV infection; however, the (SDC-1721)-gold nanoparticle conjugates displayed activity comparable to that of TAK-779. This result suggests that multivalent presentation of small molecules on gold nanoparticle surfaces can convert inactive drugs into potent therapeutics. PMID:18473457

Photodynamic effect and mechanism study of selenium-enriched phycocyanin from Spirulina platensis against liver tumours.

PubMed

Liu, Zijian; Fu, Xiang; Huang, Wei; Li, Chunxia; Wang, Xinyan; Huang, Bei

2018-03-01

Selenium-containing phycocyanin (Se-PC) has been proved to have many biological effects, including anti-inflammatory and antioxidant. In this study, we investigated the photodynamic therapy (PDT) effects of Se-PC against liver tumour in vitro and in vivo experiment. Our results demonstrated that the half lethal dose of Se-PC PDT on HepG2 cells was 100μg/ml PC containing 20% selenium. Se-PC location migration from lysosomes to mitochondria was time dependent. In in vivo experiments, the tumour inhibition rate was 75.4% in the Se-PC PDT group, compared to 52.6% in PC PDT group. Histological observations revealed that the tumour cells outside the tissue showed cellular necrosis, and those inside the tissue exhibited apoptotic nuclei and digested vacuoles in the cytoplasm after Se-PC PDT treatment. Antioxidant enzyme analysis indicated that GSH-Px activity was linked to the selenium content of Se-PC, and SOD activity was affected by PC PDT. Therefore, Se-PC PDT could induce cell death through free radical production of PDT in tumours and enhance the activity of antioxidant enzymes with selenium in vivo. The mechanism of Se-PC PDT against liver tumour involves hematocyte damage and mitochondria-mediated apoptosis accompanied with autophagy inhibition during early stage of tumour development, which displayed new prospect and offered relatively safe way for cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Chitosan nanoparticles inhibit the growth of human hepatocellular carcinoma xenografts through an antiangiogenic mechanism.

PubMed

Xu, Yinglei; Wen, Zhengshun; Xu, Zirong

2009-12-01

Chitosan nanoparticles (CNP) have demonstrated anticancer activity in vitro and in vivo by a few recent researches. However, the mechanisms involved in their potential anticancer activity remain to be elucidated. In this study, the effects of CNP on tumor growth were investigated using a model of nude mice xenografted with human hepatocellular carcinoma (HCC) (BEL-7402) cells. The results demonstrated that the treatment of these nude mice with CNP significantly inhibited tumor growth and induced tumor necrosis. Furthermore, microvessel density (MVD) determination by counting immunohistologically stained tumor microvessels suggested that CNP dose-dependent tumor suppression was correlated with the inhibition of tumor angiogenesis. Mechanistically, immunohistochemical and quantitative real-time reverse transcription-polymerase reaction assays provided evidence that CNP-mediated inhibition of tumor angiogenesis was linked to impaired levels of vascular endothelial growth factor receptor 2 (VEGFR2). Due to their low or non-toxicity, CNP and their derivatives may represent a novel class of anti-cancer drug.

Morphology of 1-methyl-1-nitrosourea induced rat mammary tumours after treatment with precursor of phytanic acid or its combination with vitamin D analogue.

PubMed

Liska, J; Macejova, D; Ondkova, S; Brtko, J

2012-01-01

The proposed therapeutical effect of phytol (PHY), a precursor of the phytanic acid (PHYA), on mammary tumours induced with 1-methyl-1-nitrosourea (MNU), was investigated in Sprague-Dawley rats in combination with vitamin D analogue, Seocalcitol (SEO). Female Sprague-Dawley rats were administered intraperitoneally with MNU (50 mg/kg of body weight) at the 46th and 52th days of age. Controls and MNU animals received propyleneglycol appropriate to their body weight. PHY (MNU + PHY) (500 mg/kg) was administered after tumour detection (approximately in 100th day of the life) three times/week. Combination of PHY with SEO (7 μg/kg per week) was administered to rats after tumour detection (approximately in 100th day of the life) until the 181st day of age. Then the animals were sacrificed, the tumours removed, and fixed in 10% formalin. Haematoxylin and eosine stained sections were evaluated under microscope. Tumour invasiveness observed in all groups of animals was ranging from 80 to 90%. Treatment with PHY alone did not inhibit the progression of the MNU induced tumours in the rat breast but it decreased the tumour burden and volume in comparison with MNU treated controls. Decreased tumour burden and volume were induced by combined treatment of PHY with SEO. Malignity and invasivity of carcinomas were not affected. No redifferentiating effect on mammary tumour cells induced by NMU after treatment with PHY alone or in combination with SEO was observed in rats. SEO alone or in combination with PHY inhibited the progression of MNU induced mammary tumours and also inhibited the increase of tumour burden and volume in comparison with MNU treated control group. However, none of the compounds, either alone or in mutual combination, reduced the malignity or the number of invasive tumours in this experimental study.

Convection-Enhanced Delivery of Carboplatin PLGA Nanoparticles for the Treatment of Glioblastoma.

PubMed

Arshad, Azeem; Yang, Bin; Bienemann, Alison S; Barua, Neil U; Wyatt, Marcella J; Woolley, Max; Johnson, Dave E; Edler, Karen J; Gill, Steven S

2015-01-01

We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas.

Convection-Enhanced Delivery of Carboplatin PLGA Nanoparticles for the Treatment of Glioblastoma

PubMed Central

Arshad, Azeem; Yang, Bin; Bienemann, Alison S.; Barua, Neil U.; Wyatt, Marcella J.; Woolley, Max; Johnson, Dave E.; Edler, Karen J.; Gill, Steven S.

2015-01-01

We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas. PMID:26186224

Therapeutically blocking Interleukin-11 Receptor-α enhances doxorubicin cytotoxicity in high grade type I endometrioid tumours.

PubMed

Winship, Amy; Van Sinderen, Michelle; Rainczuk, Katarzyna; Dimitriadis, Evdokia

2017-04-04

High grade type I endometrial cancers have poor prognosis. Interleukin (IL)11 is elevated in tumours and uterine lavage with increasing tumour grade in women. IL11 regulates cell cycle, invasion and migration and we recently demonstrated that IL11 receptor (R)α inhibition impaired low and moderate grade endometrial tumourigenesis in vivo. In this report, we hypothesized that micro-RNA(miR)-1 regulates IL11 and that IL11 promotes high grade endometrial tumour growth. We aimed to determine whether combination treatment using an anti-human IL11Rα blocking antibody (Ab) and doxorubicin chemotherapeutic impairs high grade tumour growth. MiR-1 was absent in human endometrial tumours versus human benign endometrium (n = 10/group). Transfection with miR-1 mimic restored miR-1 expression, down-regulated IL11 mRNA and impaired cell viability in grade 3-derived AN3CA human endometrial epithelial cancer cells. AN3CA cell proliferation was reduced in response to Ab and doxorubicin combination treatment versus Ab, IgG control, or doxorubicin alone. Subcutaneous xenograft tumours were established in female Balb/c athymic nude mice using AN3CA cells expressing IL11 and IL11Rα. Administration of recombinant human IL11 to mice (n = 4/group) activated IL11 downstream target, signal transducers and activators of transcription (STAT3) and significantly increased tumour growth (p < 0.05), suggesting that IL11 promotes high grade tumour growth. IL11Rα blocking Ab reduced STAT3 phosphorylation and combination treatment with doxorubicin resulted in a significant reduction in tumour growth (p < 0.05) compared to Ab, doxorubicin, or IgG control. Our data suggest that therapeutically targeting IL11Rα in combination with doxorubicin chemotherapy could inhibit high grade type I endometrioid cancer growth.

PLGA-PEG Nanoparticles Coated with Anti-CD45RO and Loaded with HDAC Plus Protease Inhibitors Activate Latent HIV and Inhibit Viral Spread

NASA Astrophysics Data System (ADS)

Tang, Xiaolong; Liang, Yong; Liu, Xinkuang; Zhou, Shuping; Liu, Liang; Zhang, Fujina; Xie, Chunmei; Cai, Shuyu; Wei, Jia; Zhu, Yongqiang; Hou, Wei

2015-10-01

Activating HIV-1 proviruses in latent reservoirs combined with inhibiting viral spread might be an effective anti-HIV therapeutic strategy. Active specific delivery of therapeutic drugs into cells harboring latent HIV, without the use of viral vectors, is a critical challenge to this objective. In this study, nanoparticles of poly(lactic-co-glycolic acid)-polyethylene glycol diblock copolymers conjugated with anti-CD45RO antibody and loaded with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) and/or protease inhibitor nelfinavir (Nel) were tested for activity against latent virus in vitro. Nanoparticles loaded with SAHA, Nel, and SAHA + Nel were characterized in terms of size, surface morphology, zeta potential, entrapment efficiency, drug release, and toxicity to ACH-2 cells. We show that SAHA- and SAHA + Nel-loaded nanoparticles can target latently infected CD4+ T-cells and stimulate virus production. Moreover, nanoparticles loaded with SAHA + NEL were capable of both activating latent virus and inhibiting viral spread. Taken together, these data demonstrate the potential of this novel reagent for targeting and eliminating latent HIV reservoirs.

Hyperglycaemia and aberrated insulin signalling stimulate tumour progression via induction of the extracellular matrix component hyaluronan.

PubMed

Twarock, Sören; Reichert, Christina; Peters, Ulrike; Gorski, Daniel J; Röck, Katharina; Fischer, Jens W

2017-08-15

Epidemiological studies have detected a higher incidence of various tumour entities in diabetic patients. However, the underlying mechanisms remain insufficiently understood. Glucose-derived pericellular and extracellular hyaluronan (HA) promotes tumour progression and development. In our study, we tested the hypothesis that a diabetic metabolic state, characterised by hyperglycaemia and concomitant aberrant insulin signalling, stimulates tumour progression via the induction of HA synthesis. In a streptozotocin-induced diabetic nude mouse tumour xenograft model, hyperglycaemia and lack of insulin caused an increased formation of tumour-associated HA-matrix, which in turn accelerated tumour progression and neoangiogenesis. This process was effectively attenuated by treatment with 4-methylumbelliferone, a pharmacological inhibitor of HA-synthesis. To define the mechanisms behind these in vivo observations, we investigated the impact of hyperglycaemia and insulin on the glucose metabolism in oesophageal squamous cell cancer cells (ESCC). Hyperglycaemia induced HA synthesis while insulin diminished HA production by directing glucose metabolites to glycolysis. Vice versa, inhibition of glycolysis, either by knockdown of the glycolytic key enzyme phosphofructokinase or by an experimental abrogation of insulin signalling (knockdown of the insulin receptor and long-term treatment with insulin) augmented HA synthesis. Consequently, these processes induced invasion, anchorage-independent growth and adhesion of ESCC to endothelial cells in vitro. Thus, the cellular shift in glucose usage from catabolism of glucose to anabolism of HA driven by hyperglycaemia and insulin resistance may represent an important link between diabetes and cancer progression. Hence, therapeutical inhibition of HA synthesis may represent a promising approach for tumour treatment in diabetic patients. © 2017 UICC.

Polysaccharide Agaricus blazei Murill stimulates myeloid derived suppressor cell differentiation from M2 to M1 type, which mediates inhibition of tumour immune-evasion via the Toll-like receptor 2 pathway.

PubMed

Liu, Yi; Zhang, Lingyun; Zhu, Xiangxiang; Wang, Yuehua; Liu, WenWei; Gong, Wei

2015-11-01

Gr-1(+) CD11b(+) myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing animals and play a critical negative role during tumor immunotherapy. Strategies for inhibition of MDSCs are expected to improve cancer immunotherapy. Polysaccharide Agaricus blazei Murill (pAbM) has been found to have anti-cancer activity, but the underlying mechanism of this is poorly understood. Here, pAbM directly activated the purified MDSCs through inducing the expression of interleukin-6 (IL-6), IL-12, tumour necrosis factor and inducible nitric oxide synthase (iNOS), CD86, MHC II, and pSTAT1 of it, and only affected natural killer and T cells in the presence of Gr-1(+) CD11b(+) monocytic MDSCs. On further analysis, we demonstrated that pAbM could selectively block the Toll-like receptor 2 (TLR2) signal of Gr-1(+) CD11b(+) MDSCs and increased their M1-type macrophage characteristics, such as producing IL-12, lowering expression of Arginase 1 and increasing expression of iNOS. Extensive study showed that Gr-1(+) CD11b(+) MDSCs by pAbM treatment had less ability to convert the CD4(+) CD25(-) cells into CD4(+) CD25(+) phenotype. Moreover, result from selective depletion of specific cell populations in xenograft mice model suggested that the anti-tumour effect of pAbM was dependent on Gr-1(+ ) CD11b(+) monocytes, nether CD8(+) T cells nor CD4(+) T cells. In addition to, pAbM did not inhibit tumour growth in TLR2(-/-) mice. All together, these results suggested that pAbM, a natural product commonly used for cancer treatment, was a specific TLR2 agonist and had potent anti-tumour effects through the opposite of the suppressive function of Gr-1(+) CD11b(+) MDSCs. © 2015 John Wiley & Sons Ltd.

Direct integrin alphavbeta6-ERK binding: implications for tumour growth.

PubMed

Ahmed, Nuzhat; Niu, Jun; Dorahy, Douglas J; Gu, Xinhua; Andrews, Sarah; Meldrum, Cliff J; Scott, Rodney J; Baker, Mark S; Macreadie, Ian G; Agrez, Michael V

2002-02-21

Blockade of the mitogen-activated protein (MAP) kinase pathway suppresses growth of colon cancer in vivo. Here we demonstrate a direct link between the extracellular signal-regulated kinase ERK2 and the growth-promoting cell adhesion molecule, integrin alphavbeta6, in colon cancer cells. Down-regulation of beta6 integrin subunit expression inhibits tumour growth in vivo and MAP kinase activity in response to serum stimulation. In alphavbeta6-expressing cells ERK2 is bound only to the beta6 subunit. The increase in cytosolic MAP kinase activity upon epidermal growth factor stimulation is all accounted for by beta6-bound ERK. Deletion of the ERK2 binding site on the beta6 cytoplasmic domain inhibits tumour growth and leads to an association between ERK and the beta5 subunit. The physical interaction between integrin alphavbeta6 and ERK2 defines a novel paradigm of integrin-mediated signalling and provides a therapeutic target for cancer treatment.

Inhibition of gold nanoparticles (AuNPs) on pathogenic biofilm formation and invasion to host cells.

PubMed

Yu, Qilin; Li, Jianrong; Zhang, Yueqi; Wang, Yufan; Liu, Lu; Li, Mingchun

2016-05-25

Owing to the growing infectious diseases caused by eukaryotic and prokaryotic pathogens, it is urgent to develop novel antimicrobial agents against clinical pathogenic infections. Biofilm formation and invasion into the host cells are vital processes during pathogenic colonization and infection. In this study, we tested the inhibitory effect of Au nanoparticles (AuNPs) on pathogenic growth, biofilm formation and invasion. Interestingly, although the synthesized AuNPs had no significant toxicity to the tested pathogens, Candida albicans and Pseudomonas aeruginosa, the nanoparticles strongly inhibited pathogenic biofilm formation and invasion to dental pulp stem cells (DPSCs). Further investigations revealed that AuNPs abundantly bound to the pathogen cells, which likely contributed to their inhibitory effect on biofilm formation and invasion. Moreover, treatment of AuNPs led to activation of immune response-related genes in DPSCs, which may enhance the activity of host immune system against the pathogens. Zeta potential analysis and polyethylene glycol (PEG)/polyethyleneimine (PEI) coating tests further showed that the interaction between pathogen cells and AuNPs is associated with electrostatic attractions. Our findings shed novel light on the application of nanomaterials in fighting against clinical pathogens, and imply that the traditional growth inhibition test is not the only way to evaluate the drug effect during the screening of antimicrobial agents.

Mediastinal germ cell tumour causing superior vena cava tumour thrombosis.

PubMed

Karanth, Suman S; Vaid, Ashok K; Batra, Sandeep; Sharma, Devender

2015-03-25

We report a rare case of a 35-year-old man who presented with a 1-week history of retrosternal chest pain of moderate intensity. A positron emission tomography CT (PET-CT) showed a large fluorodeoxy-glucose (FDG)-avid heterogeneously enhancing necrotic mass in the anterosuperior mediastinum with a focal FDG-avid thrombosis of the superior vena cava (SVC) suggestive of tumour thrombus and vascular invasion. α-Fetoprotein levels were raised (5690 IU/L). Image guided biopsy of the mediastinal mass was suggestive of non-seminomatous germ cell tumour (NSGCT). The patient received four cycles of BEP (bleomycin, etoposide and cisplatin) along with therapeutic anticoagulation with low-molecular-weight heparin. Follow-up whole body PET-CT revealed complete resolution of mediastinal mass and SVC tumour thrombosis. The documentation of FDG-PET-avid tumour thrombus resolving with chemotherapy supports the concept of circulating tumour cells being important not only in common solid tumours such as breast and colon cancer but also in relatively less common tumours such as NSGCT. The detection of circulating tumour cells could help deploy aggressive regimens upfront. 2015 BMJ Publishing Group Ltd.

Nanoparticles Affect PCR Primarily via Surface Interactions with PCR Components: Using Amino-Modified Silica-Coated Magnetic Nanoparticles as a Main Model.

PubMed

Bai, Yalong; Cui, Yan; Paoli, George C; Shi, Chunlei; Wang, Dapeng; Shi, Xianming

2015-06-24

Nanomaterials have been widely reported to affect the polymerase chain reaction (PCR). However, many studies in which these effects were observed were not comprehensive, and many of the proposed mechanisms have been primarily speculative. In this work, we used amino-modified silica-coated magnetic nanoparticles (ASMNPs, which can be collected very easily using an external magnetic field) as a model and compared them with gold nanoparticles (AuNPs, which have been studied extensively) to reveal the mechanisms by which nanoparticles affect PCR. We found that nanoparticles affect PCR primarily by binding to PCR components: (1) inhibition, (2) specifity, and (3) efficiency and yield of PCR are impacted. (1) Excess nanomaterials inhibit PCR by adsorbing to DNA polymerase, Mg(2+), oligonucleotide primers, or DNA templates. Nanoparticle surface-active groups are particularly important to this effect. (2, a) Nanomaterials do not inhibit nonspecific amplification products caused by false priming as previously surmised. It was shown that relatively low concentrations of nanoparticles inhibited the amplification of long amplicons, and increasing the amount of nanoparticles inhibited the amplification of short amplicons. This concentration phenomenon appears to be the result of the formation of "joints" upon the adsorption of ASMNPs to DNA templates. (b) Nanomaterials are able to inhibit nonspecific amplification products due to incomplete amplification by preferably adsorbing single-stranded incomplete amplification products. (3) Some types of nanomaterials, such as AuNPs, enhance the efficiency and yield of PCR because these types of nanoparticles can adsorb to single-stranded DNA more strongly than to double-stranded DNA. This behavior assists in the rapid and thorough denaturation of double-stranded DNA templates. Therefore, the interaction between the surface of nanoparticles and PCR components is sufficient to explain most of the effects of nanoparticles on PCR.

Self-assembled RNA-triple-helix hydrogel scaffold for microRNA modulation in the tumour microenvironment

NASA Astrophysics Data System (ADS)

Conde, João; Oliva, Nuria; Atilano, Mariana; Song, Hyun Seok; Artzi, Natalie

2016-03-01

The therapeutic potential of miRNA (miR) in cancer is limited by the lack of efficient delivery vehicles. Here, we show that a self-assembled dual-colour RNA-triple-helix structure comprising two miRNAs--a miR mimic (tumour suppressor miRNA) and an antagomiR (oncomiR inhibitor)--provides outstanding capability to synergistically abrogate tumours. Conjugation of RNA triple helices to dendrimers allows the formation of stable triplex nanoparticles, which form an RNA-triple-helix adhesive scaffold upon interaction with dextran aldehyde, the latter able to chemically interact and adhere to natural tissue amines in the tumour. We also show that the self-assembled RNA-triple-helix conjugates remain functional in vitro and in vivo, and that they lead to nearly 90% levels of tumour shrinkage two weeks post-gel implantation in a triple-negative breast cancer mouse model. Our findings suggest that the RNA-triple-helix hydrogels can be used as an efficient anticancer platform to locally modulate the expression of endogenous miRs in cancer.

Enhancement of antineoplastic effect and attenuation of sister chromatid exchanges by prostaglandin E2 in Ehrlich ascites tumour cells treated with cyclophosphamide in vivo.

PubMed

Mourelatos, D; Kritsi, Z; Mioglou, E; Dozi-Vassiliades, J

1993-09-01

Reduced sister chromatid exchanges (SCE) frequency in response to cyclophosphamide (CP) was observed when Ehrlich ascites tumour (EAT) cells were exposed in vivo to 2 micrograms/g body weight of prostaglandin E2 (PGE2). 1 h before i.p. injection of 5-bromodeoxyuridine (BrdUrd) adsorbed to activated charcoal, EAT-bearing mice treated i.p. with CP appeared to have increased SCE rates and cell division delays. PGE2 had no effect on survival and in inhibiting tumour growth. CP had only a slight non-significant effect on survival and in inhibiting tumour growth. In mice treated with the combined CP (5 micrograms/g bd wt) plus PGE2 (2 micrograms/g bd wt) a significant enhancement (P < 0.01) of survival time was accompanied by inhibition of tumour growth (P < 0.01) in comparison with the untreated controls. These data imply that SCEs might result from errors in a repair process which might involve a PGE2 sensitive step.

Canine perineal tumours.

PubMed

Berrocal, A; Vos, J H; van den Ingh, T S; Molenbeek, R F; van Sluijs, F J

1989-12-01

One hundred and thirty nine canine perineal tumours were histologically evaluated. The vast majority (134 tumours = 96.4%) appeared to originate from the characteristic glandular structures of this region. They were classified as well differentiated perianal gland tumours (58.3%), as moderately or poorly differentiated perianal gland tumours (21.6%) and as carcinomas without perianal gland differentiation (16.5%). Only 5 tumours (3.6%) appeared to originate from non-characteristic perineal structures. A prominent male predominance was found with respect to the perianal gland tumours, whereas the carcinomas showed a distinct female predisposition. Tumours showing perianal gland differentiation almost invariably will have a benign behaviour. The carcinomas lacking any perianal gland differentiation often show a distinct malignant behaviour with metastases to regional lymph nodes and internal organs. These malignant neoplasms showed morphological and clinical features comparable to canine anal sac gland adenocarcinomas and carcinoids in man and animals.

Development of antibody-modified chitosan nanoparticles for the targeted delivery of siRNA across the blood-brain barrier as a strategy for inhibiting HIV replication in astrocytes.

PubMed

Gu, Jijin; Al-Bayati, Karam; Ho, Emmanuel A

2017-08-01

RNA interference (RNAi)-mediated gene silencing offers a novel treatment and prevention strategy for human immunodeficiency virus (HIV) infection. HIV was found to infect and replicate in human brain cells and can cause neuroinfections and neurological deterioration. We designed dual-antibody-modified chitosan/small interfering RNA (siRNA) nanoparticles to deliver siRNA across the blood-brain barrier (BBB) targeting HIV-infected brain astrocytes as a strategy for inhibiting HIV replication. We hypothesized that transferrin antibody and bradykinin B2 antibody could specifically bind to the transferrin receptor (TfR) and bradykinin B2 receptor (B2R), respectively, and deliver siRNA across the BBB into astrocytes as potential targeting ligands. In this study, chitosan nanoparticles (CS-NPs) were prepared by a complex coacervation method in the presence of siRNA, and antibody was chemically conjugated to the nanoparticles. The antibody-modified chitosan nanoparticles (Ab-CS-NPs) were spherical in shape, with an average particle size of 235.7 ± 10.2 nm and a zeta potential of 22.88 ± 1.78 mV. The therapeutic potential of the nanoparticles was evaluated based on their cellular uptake and gene silencing efficiency. Cellular accumulation and gene silencing efficiency of Ab-CS-NPs in astrocytes were significantly improved compared to non-modified CS-NPs and single-antibody-modified CS-NPs. These results suggest that the combination of anti-Tf antibody and anti-B2 antibody significantly increased the knockdown effect of siRNA-loaded nanoparticles. Thus, antibody-mediated dual-targeting nanoparticles are an efficient and promising delivery strategy for inhibiting HIV replication in astrocytes. Graphical abstract Graphic representation of dual-antibody-conjugated chitosan nanoparticles for the targeted delivery of siRNA across the blood-brain barrier (BBB) for inhibiting HIV replication in astrocytes. a Nanoparticle delivery to the BBB and penetration. b Tf

Low tumour cell content in a lung tumour bank: implications for molecular characterisation.

PubMed

Goh, Felicia; Duhig, Edwina E; Clarke, Belinda E; McCaul, Elizabeth; Passmore, Linda; Courtney, Deborah; Windsor, Morgan; Naidoo, Rishendren; Franz, Louise; Parsonson, Kylie; Yang, Ian A; Bowman, Rayleen V; Fong, Kwun M

2017-10-01

Lung cancer encompasses multiple malignant epithelial tumour types, each with specific targetable, potentially actionable mutations, such that precision management mandates accurate tumour typing. Molecular characterisation studies require high tumour cell content and low necrosis content, yet lung cancers are frequently a heterogeneous mixture of tumour and stromal cells. We hypothesised that there may be systematic differences in tumour cell content according to histological subtype, and that this may have implications for tumour banks as a resource for comprehensive molecular characterisation studies in lung cancer. To investigate this, we estimated tumour cell and necrosis content of 4267 samples resected from 752 primary lung tumour specimens contributed to a lung tissue bank. We found that banked lung cancer samples had low tumour cell content (33%) generally, although it was higher in carcinoids (77.5%) than other lung cancer subtypes. Tumour cells comprise a variable and often small component of banked resected tumour samples, and are accompanied by stromal reaction, inflammation, fibrosis, and normal structures. This has implications for the adequacy of unselected tumour bank samples for diagnostic and molecular investigations, and further research is needed to determine whether tumour cell content has a significant impact on analytical results in studies using tissue from tumour bank resources. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Immunity to tumour antigens.

PubMed

Li, Geng; Ali, Selman A; McArdle, Stephanie E B; Mian, Shahid; Ahmad, Murrium; Miles, Amanda; Rees, Robert C

2005-01-01

During the last decade, a large number of human tumour antigens have been identified. These antigens are classified as tumour-specific shared antigens, tissue-specific differentiation antigens, overexpressed antigens, tumour antigens resulting from mutations, viral antigens and fusion proteins. Antigens recognised by effectors of immune system are potential targets for antigen-specific cancer immunotherapy. However, most tumour antigens are self-proteins and are generally of low immunogenicity and the immune response elicited towards these tumour antigens is not always effective. Strategies to induce and enhance the tumour antigen-specific response are needed. This review will summarise the approaches to discovery of tumour antigens, the current status of tumour antigens, and their potential application to cancer treatment.

Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs.

PubMed

Phillips, Roger M

2016-03-01

The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high-priority target and one of the therapeutic strategies designed to eradicate hypoxic cells in tumours is a group of compounds known collectively as hypoxia-activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (1) the ability of oxygen to either reverse or inhibit the activation process and (2) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples.

Cancer and Exercise: Warburg Hypothesis, Tumour Metabolism and High-Intensity Anaerobic Exercise.

PubMed

Hofmann, Peter

2018-01-31

There is ample evidence that regular moderate to vigorous aerobic physical activity is related to a reduced risk for various forms of cancer to suggest a causal relationship. Exercise is associated with positive changes in fitness, body composition, and physical functioning as well as in patient-reported outcomes such as fatigue, sleep quality, or health-related quality of life. Emerging evidence indicates that exercise may also be directly linked to the control of tumour biology through direct effects on tumour-intrinsic factors. Beside a multitude of effects of exercise on the human body, one underscored effect of exercise training is to target the specific metabolism of tumour cells, namely the Warburg-type highly glycolytic metabolism. Tumour metabolism as well as the tumour⁻host interaction may be selectively influenced by single bouts as well as regularly applied exercise, dependent on exercise intensity, duration, frequency and mode. High-intensity anaerobic exercise was shown to inhibit glycolysis and some studies in animals showed that effects on tumour growth might be stronger compared with moderate-intensity aerobic exercise. High-intensity exercise was shown to be safe in patients; however, it has to be applied carefully with an individualized prescription of exercise.

Study of Inhibition, Reactivation and Aging Processes of Pesticides Using Graphene Nanosheets/Gold Nanoparticles-Based Acetylcholinesterase Biosensor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Lin; Long, Linjuan; Zhang, Weiying

2012-09-10

Organophosphate (OP) and carbamate pesticides exert their toxicity via attacking the hydroxyl moiety of serine in the 'active site' of acetylcholinesterase (AChE). In this paper we developed a stable AChE biosensor based on self-assembling AChE to graphene nanosheet (GN)-gold nanoparticles (AuNPs) nanocomposite electrode for investigation of inhibition, reactivation and aging processes of different pesticides. It is confirmed that pesticides can inhibit AChE in a short time. OPs poisoning is treatable with oximes while carbarmates exposure is insensitive to oximes. The proposed electrochemical approach thus provides a new simple tool for comparison of pesticide sensitivity and guide of therapeutic intervention.

Toxicity of silver nanoparticles to Arabidopsis: Inhibition of root gravitropism by interfering with auxin pathway.

PubMed

Sun, Juzhi; Wang, Likai; Li, Shuang; Yin, Liyan; Huang, Jin; Chen, Chunli

2017-10-01

Impacts of polyvinylpyrrolidine-coated silver nanoparticles (AgNPs) on root gravitropism in Arabidopsis thaliana were investigated at the physiological, cellular, and molecular levels. Our results showed that AgNPs were taken up by the root and primarily localized at the cell wall and intercellular spaces. Root gravitropism was inhibited by exposure to AgNPs, and the inhibition in root gravitropism caused by exposure to AgNPs exhibited a dose-response relationship. Auxin accumulation was reduced in the root tips because of exposure to AgNPs. However, increased indole-3-acetic acid level could not rescue the inhibition of root gravitropism. Real-time polymerase chain reaction showed significant downregulation of expression of auxin receptor-related genes, which is the TIR1/AFB family of F-box proteins including AFB1, AFB2, AFB3, AFB5, and TIR1. Therefore, the present study suggests that AgNPs have toxicity to the model plant A. thaliana as shown by inhibition of root gravitropism along with a reduction in auxin accumulation and expression of auxin receptors. Environ Toxicol Chem 2017;36:2773-2780. © 2017 SETAC. © 2017 SETAC.

Microenvironmental autophagy promotes tumour growth.

PubMed

Katheder, Nadja S; Khezri, Rojyar; O'Farrell, Fergal; Schultz, Sebastian W; Jain, Ashish; Rahman, Mohammed M; Schink, Kay O; Theodossiou, Theodossis A; Johansen, Terje; Juhász, Gábor; Bilder, David; Brech, Andreas; Stenmark, Harald; Rusten, Tor Erik

2017-01-19

As malignant tumours develop, they interact intimately with their microenvironment and can activate autophagy, a catabolic process which provides nutrients during starvation. How tumours regulate autophagy in vivo and whether autophagy affects tumour growth is controversial. Here we demonstrate, using a well characterized Drosophila melanogaster malignant tumour model, that non-cell-autonomous autophagy is induced both in the tumour microenvironment and systemically in distant tissues. Tumour growth can be pharmacologically restrained using autophagy inhibitors, and early-stage tumour growth and invasion are genetically dependent on autophagy within the local tumour microenvironment. Induction of autophagy is mediated by Drosophila tumour necrosis factor and interleukin-6-like signalling from metabolically stressed tumour cells, whereas tumour growth depends on active amino acid transport. We show that dormant growth-impaired tumours from autophagy-deficient animals reactivate tumorous growth when transplanted into autophagy-proficient hosts. We conclude that transformed cells engage surrounding normal cells as active and essential microenvironmental contributors to early tumour growth through nutrient-generating autophagy.

Glucose starvation impairs DNA repair in tumour cells selectively by blocking histone acetylation.

PubMed

Ampferl, Rena; Rodemann, Hans Peter; Mayer, Claus; Höfling, Tobias Tim Alexander; Dittmann, Klaus

2018-03-01

Tumour cells are characterized by aerobic glycolysis and thus have high glucose consumption. Because repairing radiation-induced DNA damage is an energy-demanding process, we hypothesized that glucose starvation combined with radiotherapy could be an effective strategy to selectively target tumour cells. We glucose-starved tumour cells (A549, FaDu) in vitro and analysed their radiation-induced cell responses compared to normal fibroblasts (HSF7). Irradiation depleted intracellular ATP levels preferentially in cancer cells. Consequently, glucose starvation impaired DNA double-strand break (DSB) repair and radiosensitized confluent tumour cells but not normal fibroblasts. In proliferating tumour cells glucose starvation resulted in a reduction of proliferation, but failed to radiosensitize cells. Glucose supply was indispensable during the late DSB repair in confluent tumour cells starting approximately 13 h after irradiation, and glucose starvation inhibited radiation-induced histone acetylation, which is essential for chromatin relaxation. Sirtinol - an inhibitor of histone deacetylases - reverted the effects of glucose depletion on histone acetylation and DNA DSB repair in tumour cells. Furthermore, a glucose concentration of 2.8 mmol/L was sufficient to impair DSB repair in tumour cells and reduced their clonogenic survival under a fractionated irradiation regimen. In resting tumour cells, glucose starvation combined with irradiation resulted in the impairment of late DSB repair and the reduction of clonogenic survival, which was associated with disrupted radiation-induced histone acetylation. However, in normal cells, DNA repair and radiosensitivity were not affected by glucose depletion. Copyright © 2017 Elsevier B.V. All rights reserved.

Imaging and radiation effects of gold nanoparticles in tumour cells

PubMed Central

McQuaid, Harold N.; Muir, Mark F.; Taggart, Laura E.; McMahon, Stephen J.; Coulter, Jonathan A.; Hyland, Wendy B.; Jain, Suneil; Butterworth, Karl T.; Schettino, Giuseppe; Prise, Kevin M.; Hirst, David G.; Botchway, Stanley W.; Currell, Fred J.

2016-01-01

Gold nanoparticle radiosensitization represents a novel technique in enhancement of ionising radiation dose and its effect on biological systems. Variation between theoretical predictions and experimental measurement is significant enough that the mechanism leading to an increase in cell killing and DNA damage is still not clear. We present the first experimental results that take into account both the measured biodistribution of gold nanoparticles at the cellular level and the range of the product electrons responsible for energy deposition. Combining synchrotron-generated monoenergetic X-rays, intracellular gold particle imaging and DNA damage assays, has enabled a DNA damage model to be generated that includes the production of intermediate electrons. We can therefore show for the first time good agreement between the prediction of biological outcomes from both the Local Effect Model and a DNA damage model with experimentally observed cell killing and DNA damage induction via the combination of X-rays and GNPs. However, the requirement of two distinct models as indicated by this mechanistic study, one for short-term DNA damage and another for cell survival, indicates that, at least for nanoparticle enhancement, it is not safe to equate the lethal lesions invoked in the local effect model with DNA damage events. PMID:26787230

Release Profile and Inhibition Test of The Nanoparticles A. Paniculata Extract as Inhibitor of α-Glucosidase in The Process of Carbohydrates Breakdown Into Glucose Diabetes Mellitus

NASA Astrophysics Data System (ADS)

Imansari, Farisa; Sahlan, Muhammad; Arbianti, Rita

2017-07-01

Andrographis paniculata (A.paniculata) contain the main active substances Andrographolide which helps lower glucose levels in diabetics by inhibiting the enzyme α-glucosidase. The ability of the extract A.paniculata in lowering glucose levels will increase with the technique encapsulation with a coating of composition Chitosan-STPP as a drug delivery to the target organ. This study aimed to get an overview of A.paniculata release profile of nanoparticles in a synthetic fluid media with various concentrations of coating and inhibition testing nasty shard extract in inhibiting the enzyme α-glucosidase. This research resulted in nanoparticles by coating efficiency and loading capacity of chitosan greatest variation of 2% and 1% STPP 60% and 46.29%. chitosan greatest variation of 2% and 1% STPP 60% and 46.29%. The ability of A.paniculata extracts as α-glucosidase enzyme inhibitors has been demonstrated in this study, the percent inhibition of 33.17%.

Tumour-induced osteomalacia.

PubMed

Minisola, Salvatore; Peacock, Munro; Fukumoto, Seijii; Cipriani, Cristiana; Pepe, Jessica; Tella, Sri Harsha; Collins, Michael T

2017-07-13

Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation.

Polysaccharide Agaricus blazei Murill stimulates myeloid derived suppressor cell differentiation from M2 to M1 type, which mediates inhibition of tumour immune-evasion via the Toll-like receptor 2 pathway

PubMed Central

Liu, Yi; Zhang, Lingyun; Zhu, Xiangxiang; Wang, Yuehua; Liu, WenWei; Gong, Wei

2015-01-01

Gr-1+ CD11b+ myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing animals and play a critical negative role during tumor immunotherapy. Strategies for inhibition of MDSCs are expected to improve cancer immunotherapy. Polysaccharide Agaricus blazei Murill (pAbM) has been found to have anti-cancer activity, but the underlying mechanism of this is poorly understood. Here, pAbM directly activated the purified MDSCs through inducing the expression of interleukin-6 (IL-6), IL-12, tumour necrosis factor and inducible nitric oxide synthase (iNOS), CD86, MHC II, and pSTAT1 of it, and only affected natural killer and T cells in the presence of Gr-1+ CD11b+ monocytic MDSCs. On further analysis, we demonstrated that pAbM could selectively block the Toll-like receptor 2 (TLR2) signal of Gr-1+ CD11b+ MDSCs and increased their M1-type macrophage characteristics, such as producing IL-12, lowering expression of Arginase 1 and increasing expression of iNOS. Extensive study showed that Gr-1+ CD11b+ MDSCs by pAbM treatment had less ability to convert the CD4+ CD25− cells into CD4+ CD25+ phenotype. Moreover, result from selective depletion of specific cell populations in xenograft mice model suggested that the anti-tumour effect of pAbM was dependent on Gr-1+ CD11b+ monocytes, nether CD8+ T cells nor CD4+ T cells. In addition to, pAbM did not inhibit tumour growth in TLR2–/– mice. All together, these results suggested that pAbM, a natural product commonly used for cancer treatment, was a specific TLR2 agonist and had potent anti-tumour effects through the opposite of the suppressive function of Gr-1+ CD11b+ MDSCs. PMID:26194418

Oncogenic functions of tumour suppressor p21(Waf1/Cip1/Sdi1): association with cell senescence and tumour-promoting activities of stromal fibroblasts.

PubMed

Roninson, Igor B

2002-05-08

p21(Waf1/Cip1/Sdi1) is best known as a broad-specificity inhibitor of cyclin/cyclin-dependent kinase complexes, but p21 also interacts with many other regulators of transcription or signal transduction. p21 induction, which is mediated by p53 and by p53-independent mechanisms, is essential for the onset of cell cycle arrest in damage response and cell senescence. The effects of p21 knockout in mice and its expression patterns in human cancer are consistent with a role for p21 as both a tumour suppressor and an oncogene. Several functions of p21 are likely to promote carcinogenesis and tumour progression. These include endoreduplication and abnormal mitosis that develop in tumour cells after release from p21-induced growth arrest, the ability of p21 to inhibit apoptosis through several different mechanisms, and its ability to stimulate transcription of secreted factors with mitogenic and anti-apoptotic activities. The latter effects of p21 show close resemblance to paracrine activities of senescent cells and to tumour-promoting functions of stromal fibroblasts. Therapeutic strategies targeting the oncogenic consequences of p21 expression may provide a new approach to chemoprevention and treatment of cancer.

Synthesis of Glycyrrhetinic Acid-Modified Chitosan 5-Fluorouracil Nanoparticles and Its Inhibition of Liver Cancer Characteristics in Vitro and in Vivo

PubMed Central

Cheng, Mingrong; Gao, Xiaoyan; Wang, Yong; Chen, Houxiang; He, Bing; Xu, Hongzhi; Li, Yingchun; Han, Jiang; Zhang, Zhiping

2013-01-01

Nanoparticle drug delivery (NDDS) is a novel system in which the drugs are delivered to the site of action by small particles in the nanometer range. Natural or synthetic polymers are used as vectors in NDDS, as they provide targeted, sustained release and biodegradability. Here, we used the chitosan and hepatoma cell-specific binding molecule, glycyrrhetinic acid (GA), to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by Fourier transformed infrared spectroscopy (FT-IR) and 1H-nuclear magnetic resonance (1H-NMR). By combining GA-CTS and 5-FU (5-fluorouracil), we obtained a GA-CTS/5-FU nanoparticle, with a particle size of 217.2 nm, a drug loading of 1.56% and a polydispersity index of 0.003. The GA-CTS/5-FU nanoparticle provided a sustained release system comprising three distinct phases of quick, steady and slow release. We demonstrated that the nanoparticle accumulated in the liver. In vitro data indicated that it had a dose- and time-dependent anti-cancer effect. The effective drug exposure time against hepatic cancer cells was increased in comparison with that observed with 5-FU. Additionally, GA-CTS/5-FU significantly inhibited the growth of drug-resistant hepatoma, which may compensate for the drug-resistance of 5-FU. In vivo studies on an orthotropic liver cancer mouse model demonstrated that GA-CTS/5-FU significantly inhibited tumor growth, resulting in increased survival time. PMID:24048270

Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment

PubMed Central

Trubelja, Alen

2017-01-01

Cancer remains one of the leading causes of death, albeit enormous efforts to cure the disease. To overcome the major challenges in cancer therapy, we need to have a better understanding of the tumour microenvironment (TME), as well as a more effective means to screen anti-cancer drug leads; both can be achieved using advanced technologies, including the emerging tumour-on-a-chip technology. Here, we review the recent development of the tumour-on-a-chip technology, which integrates microfluidics, microfabrication, tissue engineering and biomaterials research, and offers new opportunities for building and applying functional three-dimensional in vitro human tumour models for oncology research, immunotherapy studies and drug screening. In particular, tumour-on-a-chip microdevices allow well-controlled microscopic studies of the interaction among tumour cells, immune cells and cells in the TME, of which simple tissue cultures and animal models are not amenable to do. The challenges in developing the next-generation tumour-on-a-chip technology are also discussed. PMID:28637915

Nanoparticle orientation to control RNA loading and ligand display on extracellular vesicles for cancer regression

NASA Astrophysics Data System (ADS)

Pi, Fengmei; Binzel, Daniel W.; Lee, Tae Jin; Li, Zhefeng; Sun, Meiyan; Rychahou, Piotr; Li, Hui; Haque, Farzin; Wang, Shaoying; Croce, Carlo M.; Guo, Bin; Evers, B. Mark; Guo, Peixuan

2018-01-01

Nanotechnology offers many benefits, and here we report an advantage of applying RNA nanotechnology for directional control. The orientation of arrow-shaped RNA was altered to control ligand display on extracellular vesicle membranes for specific cell targeting, or to regulate intracellular trafficking of small interfering RNA (siRNA) or microRNA (miRNA). Placing membrane-anchoring cholesterol at the tail of the arrow results in display of RNA aptamer or folate on the outer surface of the extracellular vesicle. In contrast, placing the cholesterol at the arrowhead results in partial loading of RNA nanoparticles into the extracellular vesicles. Taking advantage of the RNA ligand for specific targeting and extracellular vesicles for efficient membrane fusion, the resulting ligand-displaying extracellular vesicles were capable of specific delivery of siRNA to cells, and efficiently blocked tumour growth in three cancer models. Extracellular vesicles displaying an aptamer that binds to prostate-specific membrane antigen, and loaded with survivin siRNA, inhibited prostate cancer xenograft. The same extracellular vesicle instead displaying epidermal growth-factor receptor aptamer inhibited orthotopic breast cancer models. Likewise, survivin siRNA-loaded and folate-displaying extracellular vesicles inhibited patient-derived colorectal cancer xenograft.

Yessotoxin, a Marine Toxin, Exhibits Anti-Allergic and Anti-Tumoural Activities Inhibiting Melanoma Tumour Growth in a Preclinical Model

PubMed Central

Tobío, Araceli; Alfonso, Amparo; Madera-Salcedo, Iris; Botana, Luis M.

2016-01-01

Yessotoxins (YTXs) are a group of marine toxins produced by the dinoflagellates Protoceratium reticulatum, Lingulodinium polyedrum and Gonyaulax spinifera. They may have medical interest due to their potential role as anti-allergic but also anti-cancer compounds. However, their biological activities remain poorly characterized. Here, we show that the small molecular compound YTX causes a slight but significant reduction of the ability of mast cells to degranulate. Strikingly, further examination revealed that YTX had a marked and selective cytotoxicity for the RBL-2H3 mast cell line inducing apoptosis, while primary bone marrow derived mast cells were highly resistant. In addition, YTX exhibited strong cytotoxicity against the human B-chronic lymphocytic leukaemia cell line MEC1 and the murine melanoma cell line B16F10. To analyse the potential role of YTX as an anti-cancer drug in vivo we used the well-established B16F10 melanoma preclinical mouse model. Our results demonstrate that a few local application of YTX around established tumours dramatically diminished tumour growth in the absence of any significant toxicity as determined by the absence of weight loss and haematological alterations. Our data support that YTX may have a minor role as an anti-allergic drug, but reveals an important potential for its use as an anti-cancer drug. PMID:27973568

The contribution of tumour-derived exosomes to the hallmarks of cancer.

PubMed

Meehan, Katie; Vella, Laura J

2016-01-01

Exosomes are small, biologically active extracellular vesicles and over the last decade, both stromal and tumour-derived exosomes (TDE) have been implicated in cancer onset, progression and metastases. Cancer is a complex disease that is underpinned by several "cancer hallmarks", originally described by Hanahan and Weinberg in 2000 and then revised in 2011. The hallmarks of cancer comprise six biological capabilities, along with two emerging hallmarks and two enabling characteristics that facilitate tumour growth and metastatic dissemination. Ample evidence supports a clear role for TDE in four of the original biological hallmarks (sustaining proliferative signalling, resisting cell death, inducing angiogenesis and activating invasion and metastases). A less-defined role exists for TDE in evading growth suppressors, and currently, there is no evidence to suggest a role for TDE in enabling replicative immortality. TDE are intimately involved in the newly defined hallmarks of cancer and enabling characteristics, most evidently in immune inhibition and tumour-promoting inflammation, which ultimately enable escape from immune destruction and tumour progression. Herein, we discuss the role of TDE in the context of the hallmarks and enabling characteristics of cancer as defined by Hanahan and Weinberg.

Equine nasal and paranasal sinus tumours. Part 1: review of the literature and tumour classification.

PubMed

Head, K W; Dixon, P M

1999-05-01

The normal gross and histological anatomy of the equine nasal and paranasal sinuses are reviewed and the relationships between the local anatomy, the occurrence of different tumour types, and of tumour spread are examined. The histological classification of the more common equine sinonasal tumours and tumour-like lesions are discussed. Clinical and pathological descriptions of 50 more recently recorded such tumours are separately tabulated. The literature shows that equine sinonasal tumours, both endemic and sporadic, are relatively uncommon in horses, with non-neoplastic growths such as maxillary (sinus) cysts, progressive ethmoid haematoma and inflammatory nasal polyps more commonly recorded. The equine paranasal sinuses, especially the caudal maxillary sinus, are the most common sites for sinonasal tumours and, in contrast to other species, primary nasal tumours are uncommon. The more common tumour types include squamous cell carcinoma that, in some cases, arise in the oral cavity and spread to the maxillary sinuses; adenocarcinomas; bone and dental tumours; fibrosarcomas and haemangiosarcomas. Except for some benign bone tumours, there are few records of successful treatment of equine sinonasal tumours.

Curcumin-Loaded Apotransferrin Nanoparticles Provide Efficient Cellular Uptake and Effectively Inhibit HIV-1 Replication In Vitro

PubMed Central

Gandapu, Upendhar; Chaitanya, R. K.; Kishore, Golla; Reddy, Raju C.; Kondapi, Anand K.

2011-01-01

Background Curcumin (diferuloylmethane) shows significant activity across a wide spectrum of conditions, but its usefulness is rather limited because of its low bioavailability. Use of nanoparticle formulations to enhance curcumin bioavailability is an emerging area of research. Methodology/Principal Findings In the present study, curcumin-loaded apotransferrin nanoparticles (nano-curcumin) prepared by sol-oil chemistry and were characterized by electron and atomic force microscopy. Confocal studies and fluorimetric analysis revealed that these particles enter T cells through transferrin-mediated endocytosis. Nano-curcumin releases significant quantities of drug gradually over a fairly long period, ∼50% of curcumin still remaining at 6 h of time. In contrast, intracellular soluble curcumin (sol-curcumin) reaches a maximum at 2 h followed by its complete elimination by 4 h. While sol-curcumin (GI50 = 15.6 µM) is twice more toxic than nano-curcumin (GI50 = 32.5 µM), nano-curcumin (IC50<1.75 µM) shows a higher anti-HIV activity compared to sol-curcumin (IC50 = 5.1 µM). Studies in vitro showed that nano-curcumin prominently inhibited the HIV-1 induced expression of Topo II α, IL-1β and COX-2, an effect not seen with sol-curcumin. Nano-curcumin did not affect the expression of Topoisomerase II β and TNF α. This point out that nano-curcumin affects the HIV-1 induced inflammatory responses through pathways downstream or independent of TNF α. Furthermore, nano-curcumin completely blocks the synthesis of viral cDNA in the gag region suggesting that the nano-curcumin mediated inhibition of HIV-1 replication is targeted to viral cDNA synthesis. Conclusion Curcumin-loaded apotransferrin nanoparticles are highly efficacious inhibitors of HIV-1 replication in vitro and promise a high potential for clinical usefulness. PMID:21887247

Mitochondria-dependent and -independent mechanisms in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis are both regulated by interferon-gamma in human breast tumour cells.

PubMed Central

Ruiz-Ruiz, Carmen; López-Rivas, Abelardo

2002-01-01

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/APO-2L) induces apoptosis in a variety of tumour cells upon binding to death receptors TRAIL-R1 and TRAIL-R2. Here we describe the sensitization by interferon (IFN)-gamma to TRAIL-induced apoptosis in the breast tumour cell lines MCF-7 and MDA-MB231. IFN-gamma promoted TRAIL-mediated activation of caspase-8, Bcl-2 interacting domain death agonist (Bid) degradation, Bcl-2-associated X protein (Bax) translocation to mitochondria, cytochrome c release to the cytosol and activation of caspase-9 in these cell lines. No changes in the expression of TRAIL receptors were observed upon IFN-gamma treatment. Overexpression of Bcl-2 in MCF-7 cells completely inhibited IFN-gamma-induced sensitization to TRAIL-mediated cell death. Interestingly, TRAIL-induced apoptosis was also clearly enhanced by IFN-gamma in caspase-3-overexpressing MCF-7 cells, in the absence of Bax translocation to mitochondria and cytochrome c release to the cytosol. In summary, our results suggest that IFN-gamma facilitates TRAIL-induced activation of mitochondria-regulated as well as mitochondria-independent apoptotic pathways in breast tumour cells. PMID:11936954

p53 status determines the role of autophagy in pancreatic tumour development

NASA Astrophysics Data System (ADS)

Rosenfeldt, Mathias T.; O'Prey, Jim; Morton, Jennifer P.; Nixon, Colin; Mackay, Gillian; Mrowinska, Agata; Au, Amy; Rai, Taranjit Singh; Zheng, Liang; Ridgway, Rachel; Adams, Peter D.; Anderson, Kurt I.; Gottlieb, Eyal; Sansom, Owen J.; Ryan, Kevin M.

2013-12-01

Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation. Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease. The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles. Here we show, in a humanized genetically-modified mouse model of pancreatic ductal adenocarcinoma (PDAC), that autophagy's role in tumour development is intrinsically connected to the status of the tumour suppressor p53. Mice with pancreases containing an activated oncogenic allele of Kras (also called Ki-Ras)--the most common mutational event in PDAC--develop a small number of pre-cancerous lesions that stochastically develop into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 or Atg7 accumulate low-grade, pre-malignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC is blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocks tumour progression, but actually accelerates tumour onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumour growth. These findings provide considerable insight into the role of autophagy in cancer and have important implications for autophagy inhibition in cancer therapy. In this regard, we also show that treatment of mice with the autophagy inhibitor hydroxychloroquine, which is currently being used in several clinical trials, significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53.

Cannabidiol inhibits angiogenesis by multiple mechanisms

PubMed Central

Solinas, M; Massi, P; Cantelmo, AR; Cattaneo, MG; Cammarota, R; Bartolini, D; Cinquina, V; Valenti, M; Vicentini, LM; Noonan, DM; Albini, A; Parolaro, D

2012-01-01

BACKGROUND AND PURPOSE Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis. EXPERIMENTAL APPROACH Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability – through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis – and in vitro motility – both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. KEY RESULTS CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules. CONCLUSIONS AND IMPLICATIONS This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy. PMID:22624859

Cannabidiol inhibits angiogenesis by multiple mechanisms.

PubMed

Solinas, M; Massi, P; Cantelmo, A R; Cattaneo, M G; Cammarota, R; Bartolini, D; Cinquina, V; Valenti, M; Vicentini, L M; Noonan, D M; Albini, A; Parolaro, D

2012-11-01

Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis. Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability - through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis - and in vitro motility - both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules. This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

ARQ-197, a small-molecule inhibitor of c-Met, reduces tumour burden and prevents myeloma-induced bone disease in vivo.

PubMed

Lath, Darren L; Buckle, Clive H; Evans, Holly R; Fisher, Matthew; Down, Jenny M; Lawson, Michelle A; Chantry, Andrew D

2018-01-01

The receptor tyrosine kinase c-Met, its ligand HGF, and components of the downstream signalling pathway, have all been implicated in the pathogenesis of myeloma, both as modulators of plasma cell proliferation and as agents driving osteoclast differentiation and osteoblast inhibition thus, all these contribute substantially to the bone destruction typically caused by myeloma. Patients with elevated levels of HGF have a poor prognosis, therefore, targeting these entities in such patients may be of substantial benefit. We hypothesized that ARQ-197 (Tivantinib), a small molecule c-Met inhibitor, would reduce myeloma cell growth and prevent myeloma-associated bone disease in a murine model. In vitro we assessed the effects of ARQ-197 on myeloma cell proliferation, cytotoxicity and c-Met protein expression in human myeloma cell lines. In vivo we injected NOD/SCID-γ mice with PBS (non-tumour bearing) or JJN3 cells and treated them with either ARQ-197 or vehicle. In vitro exposure of JJN3, U266 or NCI-H929 cells to ARQ-197 resulted in a significant inhibition of cell proliferation and an induction of cell death by necrosis, probably caused by significantly reduced levels of phosphorylated c-Met. In vivo ARQ-197 treatment of JJN3 tumour-bearing mice resulted in a significant reduction in tumour burden, tumour cell proliferation, bone lesion number, trabecular bone loss and prevented significant decreases in the bone formation rate on the cortico-endosteal bone surface compared to the vehicle group. However, no significant differences on bone parameters were observed in non-tumour mice treated with ARQ-197 compared to vehicle, implying that in tumour-bearing mice the effects of ARQ-197 on bone cells was indirect. In summary, these res ults suggest that ARQ-197 could be a promising therapeutic in myeloma patients, leading to both a reduction in tumour burden and an inhibition of myeloma-induced bone disease.

Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response

PubMed Central

Ivarsson, K; Myllymäki, L; Jansner, K; Stenram, U; Tranberg, K-G

2005-01-01

Previous studies in our laboratory have shown that interstitial laser thermotherapy (ILT) of an experimental liver tumour is superior to surgical excision, at least partly due to a laser-induced immunological effect. The aim of the present study was to investigate the time–response relationship of the ILT-induced immunisation and the cellular response of macrophages and lymphocytes. A dimethylhydrazine-induced adenocarcinoma was transplanted into the liver of syngeneic rats. Rats with tumour were treated 6–8 days later (tumour size 0.25–0.40 cm3) with ILT of tumour or resection of the tumour-bearing lobe. Two groups of rats without tumour were treated with resection of a normal liver lobe or ILT of normal liver. A challenging tumour was implanted into the liver of each rat 2, 5 or 10 weeks after primary treatment. Rats were killed 6, 12 and 48 days (or earlier due to their condition) after challenge (n=8 in all groups). Immunohistochemical techniques were used to determine lymphocytes (CD8, CD4) and macrophages (ED1, ED2) in rats having had treatment of a primary tumour. Interstitial laser thermotherapy of the first tumour was followed by eradication of challenging tumour and absence of tumour spread. This contrasted with rapid growth and spread of challenging tumour in the other groups. In the challenging vital tumour tissue and in the interface between the tumour and surroundings, the number of ED1 macrophages and CD8 lymphocytes was higher in rats having been treated with the ILT of tumour than in those having undergone resection of the tumour-bearing lobe. The number of ED2 macrophages and CD4 lymphocytes was low and did not vary between these two groups. Interstitial laser thermotherapy elicited an immune response that eradicated a challenging tumour and was associated with increased numbers of tumour-infiltrating macrophages and CD8 lymphocytes. PMID:16091763

Feasibility study of Fe3O4/TaO x nanoparticles as a radiosensitizer for proton therapy

NASA Astrophysics Data System (ADS)

Ahn, Sang Hee; Lee, Nohyun; Choi, Changhoon; Shin, Sung Won; Han, Youngyih; Park, Hee Chul

2018-06-01

We investigated the feasibility of using multifunctional Fe3O4/TaO x (core/shell) nanoparticles, developed for use in contrast agents for computed tomography (CT) and magnetic resonance imaging (MRI), as dose-enhancing radiosensitizers. First, to verify the detectability of Fe3O4/TaO x nanoparticles in imaging, in vivo tests were conducted. Approximately 600 mg kg‑1 of 19 nm-diameter Fe3O4/TaO x nanoparticles dispersed in phosphate-buffered saline was injected into the tail vein of six Balb/c mice used as tumour (4T1 mammary carcinoma cell) models. Three mice underwent MRI (BioSpec 70/20 USR, Bruker, Billerica, MA, USA) and micro-CT (Inveon, Siemens Preclinical, Knoxville, TN, USA) before and after the injection. The difference between the pre- and post-injection images was quantified by finding the correlation coefficient. The aorta, blood vessel, and liver were clearly seen in the MRI and micro-CT images 60 min after intravenous injection of Fe3O4/TaO x nanoparticles, but the tumour region was not visible in the CT images until after 24 h. There were large differences between the pre- and post-injection images. Second, the therapeutic enhancement dose of nanomaterials was computed via Monte Carlo simulation. Monoenergetic 70- and 150 MeV proton beams irradiated x-ray contrast agent (iodine, BaSO4), MRI contrast agent (gadolinium, Fe3O4), Au, Fe3O4/TaO x (core/shell) nanoparticles and water located at the centre of a 4  ×  4  ×  4 µm3 water phantom, upon which the dose enhancement ratio (DER) (dose with/without nanoparticles) was computed. When 70 MeV protons irradiated the Au, gadolinium, Fe3O4/TaO x , Fe3O4, iodine, and BaSO4 nanoparticles, the DERs at 1 nm were 15.76, 7.68, 7.82, 6.17, 4.85, and 5.51, respectively. Fe3O4/TaO x nanoparticles have the potential to be used as a multifunctional agent that enhances tumour detection and increases the dose. Dose enhancement with Fe3O4/TaO x was half that with Au. However, Fe3O4/TaO x is

Preliminary pharmacology of galactosylated chitosan/5-fluorouracil nanoparticles and its inhibition of hepatocellular carcinoma in mice

PubMed Central

Cheng, Mingrong; Liu, Zheng; Wan, Tao; He, Bing; Zha, Bingbing; Han, Jiang; Chen, Houxiang; Yang, Fengxiao; Li, Qing; Wang, Wei; Xu, Hongzhi; Ye, Tao

2012-01-01

Biodegradable polymer nanoparticle drug delivery systems are characterized by targeted drug delivery, improved pharmacokinetic and biodistribution, enhanced drug stability and lowered side effects; these drug delivery systems are widely used for delivery of cytotoxic agents. The galactosylated chitosan (GC)/5-fluorouracil (5-FU) nanoparticle is a nanomaterial made by coupling GC, a polymer known to have the advantages described above, and 5-FU. The GC/5-FU nanoparticle is a sustained release system, it was showed that the peak time, half-life time, mean residence time (MRT) and area of under curve (AUC) of GC/5-FU were longer or more than those of the 5-FU group, but the maximum concentration (Cmax) was lower. The distribution of GC/5-FU in vivo revealed the greatest accumulation in the hepatic cancer tissues, and the hepatic cell was the target of the nanoparticles. Toxicology research showed that the toxicity of GC-5-FU was lower than that of 5-FU in mice. In vivo experiments showed that GC/5-FU can significantly inhibit tumor growth in an orthotropic liver cancer mouse model. GC/5-FU treatment can significantly lower the tumor weight and increase the survival time of mice when compared with 5-FU treatment alone. Flow cytometry and the TUNEL assay revealed that compared with 5-FU, GC/5-FU caused higher rates of G0-G1 arrest and apoptosis in hepatic cancer cells. PMID:22954702

EMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours

PubMed Central

Bornachea, Olga; Santos, Mirentxu; Martínez-Cruz, Ana Belén; García-Escudero, Ramón; Dueñas, Marta; Costa, Clotilde; Segrelles, Carmen; Lorz, Corina; Buitrago, Agueda; Saiz-Ladera, Cristina; Agirre, Xabier; Grande, Teresa; Paradela, Beatriz; Maraver, Antonio; Ariza, José M.; Prosper, Felipe; Serrano, Manuel; Sánchez-Céspedes, Montse; Paramio, Jesús M.

2012-01-01

Missense mutations in TP53 gene promote metastasis in human tumours. However, little is known about the complete loss of function of p53 in tumour metastasis. Here we show that squamous cell carcinomas generated by the specific ablation of Trp53 gene in mouse epidermis are highly metastatic. Biochemical and genome-wide mRNA and miRNA analyses demonstrated that metastases are associated with the early induction of epithelial-mesenchymal transition (EMT) and deregulated miRNA expression in primary tumours. Increased expression of miR-21 was observed in undifferentiated, prometastatic mouse tumours and in human tumours characterized by p53 mutations and distant metastasis. The augmented expression of miR-21, mediated by active mTOR and Stat3 signalling, conferred increased invasive properties to mouse keratinocytes in vitro and in vivo, whereas blockade of miR-21 in a metastatic spindle cell line inhibits metastasis development. Collectively these data identify novel molecular mechanisms leading to metastasis in vivo originated by p53 loss in epithelia. PMID:22666537

Pharmacology of liposomal vincristine in mice bearing L1210 ascitic and B16/BL6 solid tumours.

PubMed Central

Mayer, L. D.; Masin, D.; Nayar, R.; Boman, N. L.; Bally, M. B.

1995-01-01

Vincristine pharmacokinetic, tumour uptake and therapeutic characteristics were investigated here in order to elucidate the processes underlying the enhanced efficacy observed for vincristine entrapped in small (120 nm) distearoylphosphatidylcholine/cholesterol liposomes. Plasma vincristine levels after intravenous (i.v.) injection are elevated more than 100-fold in the liposomal formulation compared with free drug in tumour-bearing as well as non-tumour-bearing mice over 24 h. Biodistribution studies demonstrate that the extent and duration of tumour exposure to vincristine is dramatically improved when the drug is administered i.v. in liposomal form. Specifically, 72 h trapezoidal area under the curve values for liposomal vincristine in the murine L1210 ascitic and B16/BL6 solid tumours are 12.9- to 4.1-fold larger, respectively, than observed for free drug. Similar to previous results with the L1210 model, increased drug delivery to the B16 tumour results in significant inhibition of tumour growth, whereas no anti-tumour activity is observed with free vincristine. Comparisons of drug and liposomal lipid accumulation in tumour and muscle tissue indicate that the enhanced efficacy of liposomal vincristine is related predominantly to drug delivered by liposomes to the tumour site rather than drug released from liposomes in the circulation. Consequently, improvements in liposomal vincristine formulations must focus on factors that increase uptake of liposomes into tumour sites as well as enhance liposomal drug retention in the circulation. PMID:7880728

Safety and feasibility of targeted agent combinations in solid tumours.

PubMed

Park, Sook Ryun; Davis, Myrtle; Doroshow, James H; Kummar, Shivaani

2013-03-01

The plethora of novel molecular-targeted agents (MTAs) has provided an opportunity to selectively target pathways involved in carcinogenesis and tumour progression. Combination strategies of MTAs are being used to inhibit multiple aberrant pathways in the hope of optimizing antitumour efficacy and to prevent development of resistance. While the selection of specific agents in a given combination has been based on biological considerations (including the role of the putative targets in cancer) and the interactions of the agents used in combination, there has been little exploration of the possible enhanced toxicity of combinations resulting from alterations in multiple signalling pathways in normal cell biology. Owing to the complex networks and crosstalk that govern normal and tumour cell proliferation, inhibiting multiple pathways with MTA combinations can result in unpredictable disturbances in normal physiology. This Review focuses on the main toxicities and the lack of tolerability of some common MTA combinations, particularly where evidence of enhanced toxicity compared to either agent alone is documented or there is development of unexpected toxicity. Toxicities caused by MTA combinations highlight the need to introduce new preclinical testing paradigms early in the drug development process for the assessment of chronic toxicities resulting from such combinations.

Phyllodes tumours

PubMed Central

Parker, S; Harries, S

2001-01-01

Phyllodes tumours are rare fibroepithelial lesions that account for less than 1% of all breast neoplasms. With the non-operative management of fibroadenomas widely adopted, the importance of phyllodes tumours today lies in the need to differentiate them from other benign breast lesions. All breast lumps should be triple assessed and the diagnosis of a phyllodes tumour considered in women, particularly over the age of 35 years, who present with a rapidly growing "benign" breast lump. Treatment can be by either wide excision or mastectomy provided histologically clear specimen margins are ensured. Nodal metastases are rare and routine axillary dissection is not recommended. Few reliable clinical and histological prognostic factors have been identified. Local recurrence occurs in approximately 15% of patients and is more common after incomplete excision. It can usually be controlled by further surgery. Repeated local recurrence has been reported without the development of distant metastases or reduced survival. Approximately 20% of patients with malignant phyllodes tumours develop distant metastases. Long term survival with distant metastases is rare. The role of chemotherapy, radiotherapy, and hormonal manipulation in both the adjuvant and palliative settings remain to be defined.


Keywords: benign breast disease; fibroadenoma; phyllodes tumour PMID:11423590

Copper Nanoparticles: Synthesis and Biological Activity

NASA Astrophysics Data System (ADS)

Satyvaldiev, A. S.; Zhasnakunov, Z. K.; Omurzak, E.; Doolotkeldieva, T. D.; Bobusheva, S. T.; Orozmatova, G. T.; Kelgenbaeva, Z.

2018-01-01

By means of XRD and FESEM analysis, it is established that copper nanoparticles with sizes less than 10 nm are formed during the chemical reduction, which form aggregates mainly with spherical shape. Presence of gelatin during the chemical reduction of copper induced formation of smaller size distribution nanoparticles than that of nanoparticles synthesized without gelatin and it can be related to formation of protective layer. Synthesized Cu nano-powders have sufficiently high activity against the Erwinia amylovora bacterium, and the bacterial growth inhibition depends on the Cu nanoparticles concentration. At a concentration of 5 mg / ml of Cu nanoparticles, the exciter growth inhibition zone reaches a maximum value within 72 hours and the lysis zone is 20 mm, and at a concentration of 1 mg / ml this value is 16 mm, which also indicates the significant antibacterial activity of this sample.

Long non-coding RNA NRON is downregulated in HCC and suppresses tumour cell proliferation and metastasis.

PubMed

Yao, Zhicheng; Xiong, Zhiyong; Li, Ruixi; Liang, Hao; Jia, Changchang; Deng, Meihai

2018-05-14

Dysregulation of long non-coding RNAs is a newly identified mechanism for tumour progression. Previous studies have suggested that the nuclear factor of activated T cells (NFAT) gene plays a very important role in cancer growth and metastasis. However, lncNRON is a newly identified repressor of NFAT, and its function is largely unknown, especially in hepatocellular carcinoma (HCC). Therefore, the expression levels of lncNRON in 215 pairs of HCC tissue were evaluated by qRT-PCR, and its relationship to clinicopathological parameters, recurrence, and survival was analysed. Furthermore, stably overexpressing lncNRON cell lines were constructed and evaluated for cell phenotype. Finally, we detected epithelial-to-mesenchymal transition (EMT) proteins to determine the underlying mechanism involved in lncNRON function. We observed that lncNRON was downregulated in HCC tumour tissues; low lncNRON expression was associated with poor tumour differentiation and the presence of vascular tumour thrombus, which tended to result in poor clinical outcomes, as demonstrated by the recurrence rate and survival curves. Functional analysis showed that lncNRON overexpression impaired colony formation and cell viability and inhibited cell migration and invasion. A study using tumour-bearing mice showed that lncNRON markedly limited tumour growth and lung metastasis in vivo. Importantly, western blot analysis revealed that the expression of the EMT-related epithelial marker, E-cadherin, increased, whereas the expression of mesenchymal markers N-cadherin, snail, and vimentin was attenuated by lncNRON overexpression in HCC cells. Therefore, lower lncNRON expression indicates a poorer clinical outcome in HCC. LncNRON overexpression can suppress HCC growth and metastasis via inhibiting the EMT, and lncNRON may function as a new HCC prognostic marker. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Synthesis and characterization of polystyrene embolization particles doped with tantalum oxide nanoparticles for X-ray contrast.

PubMed

Morrison, Rachel; Thompson, James; Bird, Luke; Hill, Mark A; Townley, Helen

2015-08-01

Radiopaque and fluorescent embolic particles have been synthesized and characterised to match the size of vasculature found in tumours to ensure effective occlusion of the vessels. A literature search showed that the majority of vessels surrounding a tumour were less than 50 µm and therefore polydispersed polystyrene particles with a peak size of 50 µm have been synthesised. The embolic particles contain 5-8 nm amorphous tantalum oxide nanoparticles which provide X-ray contrast. Embolic particles containing up to 9.4 wt% tantalum oxide were prepared and showed significant contrast compared to the undoped polystyrene particles. The X-ray contrast of the embolic particles was shown to be linear (R(2) = 0.9) with respect to the concentration of incorporated tantalum nanoparticles. A model was developed which showed that seventy-five 50 µm embolic particles containing 10% tantalum oxide could provide the same contrast as 5 cm of bone. Therefore, the synthesized particles would provide sufficient X-ray contrast to enable visualisation within a tumour.

Mesenchymal stromal cells (MSCs) and colorectal cancer: a troublesome twosome for the anti-tumour immune response?

PubMed Central

O'Malley, Grace; Heijltjes, Madelon; Houston, Aileen M.; Rani, Sweta; Ritter, Thomas; Egan, Laurence J.; Ryan, Aideen E.

2016-01-01

The tumour microenvironment (TME) is an important factor in determining the growth and metastasis of colorectal cancer, and can aid tumours by both establishing an immunosuppressive milieu, allowing the tumour avoid immune clearance, and by hampering the efficacy of various therapeutic regimens. The tumour microenvironment is composed of many cell types including tumour, stromal, endothelial and immune cell populations. It is widely accepted that cells present in the TME acquire distinct functional phenotypes that promote tumorigenesis. One such cell type is the mesenchymal stromal cell (MSC). Evidence suggests that MSCs exert effects in the colorectal tumour microenvironment including the promotion of angiogenesis, invasion and metastasis. MSCs immunomodulatory capacity may represent another largely unexplored central feature of MSCs tumour promoting capacity. There is considerable evidence to suggest that MSCs and their secreted factors can influence the innate and adaptive immune responses. MSC-immune cell interactions can skew the proliferation and functional activity of T-cells, dendritic cells, natural killer cells and macrophages, which could favour tumour growth and enable tumours to evade immune cell clearance. A better understanding of the interactions between the malignant cancer cell and stromal components of the TME is key to the development of more specific and efficacious therapies for colorectal cancer. Here, we review and explore MSC- mediated mechanisms of suppressing anti-tumour immune responses in the colon tumour microenvironment. Elucidation of the precise mechanism of immunomodulation exerted by tumour-educated MSCs is critical to inhibiting immunosuppression and immune evasion established by the TME, thus providing an opportunity for targeted and efficacious immunotherapy for colorectal cancer growth and metastasis. PMID:27542276

Efficacy of punarnavine in restraining organ-specific tumour progression in 4T1-induced murine breast tumour model.

PubMed

George Kallivalappil, Gilcy; Kuttan, Girija

2018-05-17

Most of the breast cancer deaths occur when cancer cells depart from their tumour of origin and spread systemically and colonise distant organs. The present study was to find out whether punarnavine, the quinolizidine alkaloid, with already proven antimetastatic effect on spontaneous B16F10 pulmonary metastasis has got any effect on a drastic organ-specific breast cancer spread. For the study, we selected a syngenic mouse 4T1 breast tumour model that mimics stage four of human breast cancer. The metastatic progression of 4T1 to lymph nodes, lungs, and liver was reduced by punarnavine (40 mg/kg body weight) administration in BALB/c mice. This was evident from the histopathology of these organs as well as from the reduction in the metastatic cell density of cultured 6-thioguanine-resistant 4T1 cells in the punarnavine-treated group compared to the control group. There was also a significant (p < 0.0001) inhibition of the primary breast tumour growth in the orthotopic site of induction with a simultaneous increase (p < 0.0001) in the life span of treated animals. The assessment of biochemical parameters such as hydroxyproline, hexosamine, uronic acid, sialic acid and γ-glutamyl transferase and the analysis of various cytokines VEGF, IL-1β, TNF-α and GM-CSF showed a similar pattern of reduction in punarnavine (p < 0.0001) treated group compared to the control group. The gene expression study revealed the inhibitory effect of punarnavine on the major genes MMP-2, MMP-9, TIMP-1, TIMP-2 and VEGF involved in the metastatic process. These findings undeniably proved the potential of this quinolizidine alkaloid in combating breast tumour development and its progression in the studied murine model.

Zinc oxide nanoparticles inhibit murine photoreceptor-derived cell proliferation and migration via reducing TGF-β and MMP-9 expression in vitro.

PubMed

Guo, Da Dong; Li, Qing Ning; Li, Chun Min; Bi, Hong Sheng

2015-04-01

To investigate behaviour and expression of transforming growth factor-β (TGF-β) and matrix metalloproteinases (MMP-9) in murine photoreceptor-derived cells (661W) after incubation with zinc oxide (ZnO) nanoparticles. We explored effects of ZnO nanoparticles on 661W cells using a real-time cell electronic sensing system, flow cytometry, multiple function microplate reading, real-time quantitative PCR detection system and enzyme-linked immunosorbent assay respectively. Our results indicate that ZnO nanoparticles induced overload of calcium and reactive oxygen species within cells, causing formation of apoptotic bodies, disruption of cell cycle distribution, and reduction in expression of TGF-β and MMP-9, to suppress cell proliferation and migration. Our findings show that disruption of intracellular calcium homoeostasis and overproduction of reactive oxygen species were closely associated with reduction of TGF-β and MMP-9 in 661W cells under ZnO nanoparticle treatment. Results of our study indicate that ZnO nanoparticles suppressed cell proliferation and migration, and reduced production of TGF-β and MMP-9 at both gene and protein levels. Our findings contribute to the understanding of the molecular mechanisms that reduced TGF-β and MMP-9 levels inhibit cell proliferation and migration under ZnO nanoparticle influence. © 2015 John Wiley & Sons Ltd.

Effects of phytoestrogens on the trophoblast tumour cell lines BeWo and Jeg3.

PubMed

Plessow, D; Waldschläger, J; Richter, D U; Jeschke, U; Bruer, G; Briese, V; Friese, K

2003-01-01

Phytoestrogens are a diverse group of nonsteroidal plant compounds that occur naturally in many plants. Because they possess a ring system similar to estrogens they are able to bind to estrogen receptors in humans. With this study we tested the effects of the phytoestrogens genistein and daidzein in cell proliferation and the production of progesterone and hCG in trophoblast tumour cells of the cell lines BeWo and Jeg3. The phytoestrogens genistein and daidzein were incubated in different concentrations with trophoblast tumour cells. Untreated cells were used as controls. At designated times, aliquots were removed and tested for progesterone and hCG. In addition we tested the effects of phytoestrogens on cell proliferation. Different concentrations of genistein and daidzein were cultivated with trophoblast tumour cells. After designated times, 1 microCi thymidin-(methyl-3H) was added. Methyl-3H thymidin incorporation was tested and compared to incorporation results of untreated cells. With this study we could show that the production of the steroid hormone progesterone and the protein hormone hCG is influenced by the phytoestrogens genistein and daidzein in trophoblast tumour cells of the cell lines BeWo and Jeg3. We found a correlation between the effects on the proliferation and the production of progesterone and hCG at high concentrations of genistein and daidzein in the cell lines tested. With low concentrations of genistein and daidzein we observed a stimulation of the production of hCG and a weak inhibition of proliferation in both cell lines BeWo and Jeg3. The results obtained with this study suggest that only high doses of phytoestrogens (> 1 mumol/ml) can reduce the proliferation of trophoblast tumour cells significantly. Low doses of phytoestrogens induced a higher hCG production in both cell lines tested. Although high hCG production did not lead to a higher proliferation rate of the tumour cells tested, hCG is able to induce neovascularisation in tumour

Composite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine.

PubMed

Muta, Yu; Fujita, Yoshihisa; Sumiyama, Kenta; Sakurai, Atsuro; Taketo, M Mark; Chiba, Tsutomu; Seno, Hiroshi; Aoki, Kazuhiro; Matsuda, Michiyuki; Imajo, Masamichi

2018-06-05

Acting downstream of many growth factors, extracellular signal-regulated kinase (ERK) plays a pivotal role in regulating cell proliferation and tumorigenesis, where its spatiotemporal dynamics, as well as its strength, determine cellular responses. Here, we uncover the ERK activity dynamics in intestinal epithelial cells (IECs) and their association with tumour characteristics. Intravital imaging identifies two distinct modes of ERK activity, sustained and pulse-like activity, in IECs. The sustained and pulse-like activities depend on ErbB2 and EGFR, respectively. Notably, activation of Wnt signalling, the earliest event in intestinal tumorigenesis, augments EGFR signalling and increases the frequency of ERK activity pulses through controlling the expression of EGFR and its regulators, rendering IECs sensitive to EGFR inhibition. Furthermore, the increased pulse frequency is correlated with increased cell proliferation. Thus, ERK activity dynamics are defined by composite inputs from EGFR and ErbB2 signalling in IECs and their alterations might underlie tumour-specific sensitivity to pharmacological EGFR inhibition.

Extracts of Crinum latifolium inhibit the cell viability of mouse lymphoma cell line EL4 and induce activation of anti-tumour activity of macrophages in vitro.

PubMed

Nguyen, Hoang-Yen T; Vo, Bach-Hue T; Nguyen, Lac-Thuy H; Bernad, Jose; Alaeddine, Mohamad; Coste, Agnes; Reybier, Karine; Pipy, Bernard; Nepveu, Françoise

2013-08-26

Crinum latifolium L. (CL) leaf extracts have been traditionally used in Vietnam and are now used all over the world for the treatment of prostate cancer. However, the precise cellular mechanisms of the action of CL extracts remain unclear. To examine the effects of CL samples on the anti-tumour activity of peritoneal murine macrophages. The properties of three extracts (aqueous, flavonoid, alkaloid), one fraction (alkaloid), and one pure compound (6-hydroxycrinamidine) obtained from CL, were studied (i) for redox capacities (DPPH and bleaching beta-carotene assays), (ii) on murine peritoneal macrophages (MTT assay) and on lymphoma EL4-luc2 cells (luciferine assay) for cytotoxicity, (iii) on macrophage polarization (production of ROS and gene expression by PCR), and (iv) on the tumoricidal functions of murine peritoneal macrophages (lymphoma cytotoxicity by co-culture with syngeneic macrophages). The total flavonoid extract with a high antioxidant activity (IC50=107.36 mg/L, DPPH assay) showed an inhibitory action on cancer cells. Alkaloid extracts inhibited the proliferation of lymphoma cells either by directly acting on tumour cells or by activating of the tumoricidal functions of syngeneic macrophages. The aqueous extract induced mRNA expression of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin 6 (IL-6) indicating differentiation of macrophages into pro-inflammatory M1 polarized macrophages. The total flavonoid, alkaloid extracts and an alkaloid fraction induced the expression of the formyl peptide receptor (FPR) on the surface of the polarized macrophages that could lead to the activation of macrophages towards the M1 phenotype. Aqueous and flavonoid extracts enhanced NADPH quinine oxido-reductase 1 (NQO1) mRNA expression in polarized macrophages which could play an important role in cancer chemoprevention. All the samples studied were non-toxic to normal living cells and the pure alkaloid tested, 6-hydroxycrinamidine, was not

Novel somatic and germline mutations in intracranial germ cell tumours.

PubMed

Wang, Linghua; Yamaguchi, Shigeru; Burstein, Matthew D; Terashima, Keita; Chang, Kyle; Ng, Ho-Keung; Nakamura, Hideo; He, Zongxiao; Doddapaneni, Harshavardhan; Lewis, Lora; Wang, Mark; Suzuki, Tomonari; Nishikawa, Ryo; Natsume, Atsushi; Terasaka, Shunsuke; Dauser, Robert; Whitehead, William; Adekunle, Adesina; Sun, Jiayi; Qiao, Yi; Marth, Gábor; Muzny, Donna M; Gibbs, Richard A; Leal, Suzanne M; Wheeler, David A; Lau, Ching C

2014-07-10

Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries, with peak incidence near the time of puberty. About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3-4:1 overall, but is even higher for tumours located in the pineal region. Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis.

PubMed

Annibali, Daniela; Whitfield, Jonathan R; Favuzzi, Emilia; Jauset, Toni; Serrano, Erika; Cuartas, Isabel; Redondo-Campos, Sara; Folch, Gerard; Gonzàlez-Juncà, Alba; Sodir, Nicole M; Massó-Vallés, Daniel; Beaulieu, Marie-Eve; Swigart, Lamorna B; Mc Gee, Margaret M; Somma, Maria Patrizia; Nasi, Sergio; Seoane, Joan; Evan, Gerard I; Soucek, Laura

2014-08-18

Gliomas are the most common primary tumours affecting the adult central nervous system and respond poorly to standard therapy. Myc is causally implicated in most human tumours and the majority of glioblastomas have elevated Myc levels. Using the Myc dominant negative Omomyc, we previously showed that Myc inhibition is a promising strategy for cancer therapy. Here, we preclinically validate Myc inhibition as a therapeutic strategy in mouse and human glioma, using a mouse model of spontaneous multifocal invasive astrocytoma and its derived neuroprogenitors, human glioblastoma cell lines, and patient-derived tumours both in vitro and in orthotopic xenografts. Across all these experimental models we find that Myc inhibition reduces proliferation, increases apoptosis and remarkably, elicits the formation of multinucleated cells that then arrest or die by mitotic catastrophe, revealing a new role for Myc in the proficient division of glioma cells.

Systematic assessment of blood circulation time of functionalized upconversion nanoparticles in the chick embryo

NASA Astrophysics Data System (ADS)

Nadort, Annemarie; Liang, Liuen; Grebenik, Ekaterina; Guller, Anna; Lu, Yiqing; Qian, Yi; Goldys, Ewa; Zvyagin, Andrei

2015-12-01

Nanoparticle-based delivery of drugs and contrast agents holds great promise in cancer research, because of the increased delivery efficiency compared to `free' drugs and dyes. A versatile platform to investigate nanotechnology is the chick embryo chorioallantoic membrane tumour model, due to its availability (easy, cheap) and accessibility (interventions, imaging). In our group, we developed this model using several tumour cell lines (e.g. breast cancer, colon cancer). In addition, we have synthesized in-house silica coated photoluminescent upconversion nanoparticles with several functional groups (COOH, NH2, PEG). In this work we will present the systematic assessment of their in vivo blood circulation times. To this end, we injected chick embryos grown ex ovo with the functionalized UCNPs and obtained a small amount of blood at several time points after injection to create blood smears The UCNP signal from the blood smears was quantified using a modified inverted microscope imaging set-up. The results of this systematic study are valuable to optimize biochemistry protocols and guide nanomedicine advancement in the versatile chick embryo tumour model.

A Feedback Control Model of Comprehensive Therapy for Treating Immunogenic Tumours

NASA Astrophysics Data System (ADS)

Tang, Biao; Xiao, Yanni; Tang, Sanyi; Cheke, Robert A.

Surgery is the traditional method for treating cancers, but it often fails to cure patients for complex reasons so new therapeutic approaches that include both surgery and immunotherapy have recently been proposed. These have been shown to be effective, clinically, in inhibiting cancer cells while allowing retention of immunologic memory. This comprehensive strategy is guided by whether a population of tumour cells has or has not exceeded a threshold density. Conditions for successful control of tumours in an immune tumour system were modeled and the related dynamics were addressed. A mathematical model with state-dependent impulsive interventions is formulated to describe combinations of surgery with immunotherapy. By analyzing the properties of the Poincaré map, we examine the global dynamics of the immune tumour system with state-dependent feedback control, including the existence and stability of the semi-trivial order-1 periodic solution and the positive order-k periodic solution. The main results showed that surgery alone can only control the tumour size below a certain level while there is no immunologic memory. If comprehensive therapy involving combining surgery with immunotherapy is considered, then not only can the cancers be controlled below a certain level, but the immune system can also retain its activity. The existence of positive order-k periodic solutions implies that periodical therapy is needed to control the cancers. However, choosing the treatment frequency and the strength of the therapy remains challenging, and hence a strategy of individual-based therapy is suggested.

Innovative approach for urease inhibition by Ficus carica extract-fabricated silver nanoparticles: An in vitro study.

PubMed

Borase, Hemant P; Salunkhe, Rahul B; Patil, Chandrashekhar D; Suryawanshi, Rahul K; Salunke, Bipinchandra K; Wagh, Nilesh D; Patil, Satish V

2015-01-01

In the present study, a rapid, low-cost, and ecofriendly method of stable silver nanoparticles (AgNPs) synthesis using leaves extract of Ficus carica (F. carica), a plant with diverse metabolic consortium, is reported for the first time. An absorption peak at 422 nm in UV-Vis spectroscopy, a spherical shape with an average size of 21 nm in transmission electron microscopy, and crystalline nature in X-ray powder diffraction studies were observed for the synthesized AgNPs. Fourier transform infrared analysis indicated that proteins of F. carica might have a vital role in AgNP synthesis and stabilization. AgNPs were found to inhibit urease, a key enzyme responsible for the survival and pathogenesis of the bacterium, Helicobacter pylori. Inhibition of urease by AgNPs was monitored spectrophotometrically by the evaluation of ammonia release. The urease inhibition potential of AgNPs can be explored in the treatment of H. pylori by preparing novel combinations of standard drugs with AgNPs- or AgNPs-encapsulated drug molecules. © 2015 International Union of Biochemistry and Molecular Biology, Inc.

Effects of the flavonoid drug quercetin on the response of human prostate tumours to hyperthermia in vitro and in vivo.

PubMed

Asea, A; Ara, G; Teicher, B A; Stevenson, M A; Calderwood, S K

2001-01-01

Tumour hyperthermia, although potentially a powerful therapeutic agent and radiation sensitizer, is hindered by a number of considerations including inhomogeneous heating of deep seated tumours due to energy deposition and perfusion issues. One solution is to design hyperthermia sensitizers to amplify the effects of hyperthermia, particularly at cold spots within the tumour undergoing treatment. This study examined the use of Quercetin, a flavonoid drug shown previously to antagonize the expression of HSP72 and induce apoptosis as a sensitizer of prostate cancer growth in vivo. Quercetin dose-dependently suppressed PC-3 tumour growth in vitro and in vivo. When combined in a treatment protocol with hyperthermia, quercetin drastically inhibited tumour growth and potently amplified the effects of hyperthermia on two prostate tumour types, PC-3 and DU-145 in vivo. These experiments, thus, suggest the use of Quercetin as a hyperthermia sensitizer in the treatment of prostate carcinoma.

Silica nanoparticles induce cytokine responses in lung epithelial cells through activation of a p38/TACE/TGF-α/EGFR-pathway and NF-κΒ signalling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skuland, Tonje, E-mail: tonje.skuland@fhi.no; Øvrevik, Johan; Låg, Marit

2014-08-15

Amorphous silica nanoparticles (SiNPs) have previously been shown to induce marked cytokine (interleukin-6; IL-6 and interleukin-8; CXCL8/IL-8) responses independently of particle uptake in human bronchial epithelial BEAS-2B cells. In this study the involvement of the mitogen-activated protein kinases (MAP-kinases), nuclear factor-kappa Β (NF-κΒ) and in particular tumour necrosis factor-α converting enzyme (TACE) and—epidermal growth factor receptor (EGFR) signalling pathways were examined in triggering of IL-6 and CXCL8 release after exposure to a 50 nm silica nanoparticle (Si50). Exposure to Si50 increased phosphorylation of NF-κΒ p65 and MAP-kinases p38 and JUN-N-terminal protein kinase pathways (JNK), but not extracellular signal regulated kinasesmore » (ERK). Inhibition of NF-κΒ and p38 reduced the cytokine responses to Si50, whereas neither JNK- nor ERK-inhibition exerted any significant effect on the responses to Si50. Increases in membrane-bound transforming growth factor-α (TGF-α) release and EGFR phosphorylation were also observed after Si50 exposure, and pre-treatment with inhibitors of these pathways reduced the release of IL-6 and CXCL8, but did not affect the Si50-induced phosphorylation of p38 and p65. In contrast, p38-inhibition partially reduced Si50-induced TGF-α release, while the p65-inhibition was without effect. Overall, our results indicate that Si50-induced IL-6 and CXCL8 responses in BEAS-2B cells were regulated through combined activation of several pathways, including NF-κΒ and p38/TACE/TGF-α/EGFR signalling. The study identifies critical, initial events in the triggering of pro-inflammatory responses by nanoparticles. - Highlights: • Silica nanoparticles induce IL-6 and CXCL8 via NFκB and MAPKinase p38 in BEAS-2B • Silica nanoparticles induce release of the EGF-receptor ligand TGF-α • TGF-α release contributes to the IL-6 and CXCL8 release • Phosphorylation of p38 is involved in release of TGF-α.« less

Enhancement of oral bioavailability of rivastigmine with quercetin nanoparticles by inhibiting CYP3A4 and esterases.

PubMed

Palle, Suresh; Neerati, Prasad

2017-04-01

Quercetin is a well-known flavonoid, has pharmacokinetic interaction with ester drugs due to its capability of esterase inhibition in the gut and liver. However, the interaction between quercetin nanoparticles (NQC) and rivastigmine has not been reported. Hence, the present study was performed to evaluate the effect of quercetin alone and its nanoparticles on the pharmacokinetics of rivastigmine in rats. NQC prepared by antisolvent precipitation method. The influence of quercetin on the pharmacokinetics of rivastigmine was evaluated by following methods i.e. in vitro inhibitory effect on esterase enzyme in rat liver microsomes and in vitro assessment of CYP3A activity using erythromycin-N-demethylase (EMD) assay. To confirm these findings, an in vivo pharmacokinetic study of orally administered rivastigmine in rats with quercetin and NQC pretreatments was performed. The size of NQC was observed below 300nm. Quercetin significantly (p<0.05) inhibited the esterase-mediated metabolism of rivastigmine. In in vitro assessment of CYP3A activity model the erythromycin-N-demethylation (EMD) levels in quercetin treated group were significantly reduced (p<0.05). C max , AUC 0-t and AUC 0- ∞ of rivastigmine were found to be increased in quercetin and NQC pretreated groups. Further, the CL/F and Vd/F of rivastigmine were significantly decreased. The results revealed that enhanced bioavailability of rivastigmine might be caused by the combination of their effects due to CYP3A and esterase inhibition, Therefore, concomitant administration of NQC influences the bioavailability of rivastigmine and also has synergetic effect in the treatment of Alzheimer's disease. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

LACTB is a tumour suppressor that modulates lipid metabolism and cell state.

PubMed

Keckesova, Zuzana; Donaher, Joana Liu; De Cock, Jasmine; Freinkman, Elizaveta; Lingrell, Susanne; Bachovchin, Daniel A; Bierie, Brian; Tischler, Verena; Noske, Aurelia; Okondo, Marian C; Reinhardt, Ferenc; Thiru, Prathapan; Golub, Todd R; Vance, Jean E; Weinberg, Robert A

2017-03-30

Post-mitotic, differentiated cells exhibit a variety of characteristics that contrast with those of actively growing neoplastic cells, such as the expression of cell-cycle inhibitors and differentiation factors. We hypothesized that the gene expression profiles of these differentiated cells could reveal the identities of genes that may function as tumour suppressors. Here we show, using in vitro and in vivo studies in mice and humans, that the mitochondrial protein LACTB potently inhibits the proliferation of breast cancer cells. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. This is achieved, at least in part, through reduction of the levels of mitochondrial phosphatidylserine decarboxylase, which is involved in the synthesis of mitochondrial phosphatidylethanolamine. These observations uncover a novel mitochondrial tumour suppressor and demonstrate a connection between mitochondrial lipid metabolism and the differentiation program of breast cancer cells, thereby revealing a previously undescribed mechanism of tumour suppression.

Multifocal multi-site Warthin tumour.

PubMed

Hilton, Jennifer M; Phillips, John S; Hellquist, Henrik B; Premachandra, Don J

2008-12-01

The unique case of a 55-year-old man with multifocal adenolymphoma (Warthin's tumour) of both parotid glands, the neck and post-nasal space is presented. Warthin tumour is almost exclusively a parotid tumour but is known to be bilateral in 7-10% of cases and multifocal in 2% of cases. Most extraglandular Warthin tumours have been located in neck lymph nodes and only a few cases have been reported from other sites. The presented case is unique in having synchronous and metachronous Warthin tumours, as well as one of the tumours being neither truly parotid, nor within a lymph node.

Non-invasive mapping of deep-tissue lymph nodes in live animals using a multimodal PET/MRI nanoparticle

NASA Astrophysics Data System (ADS)

Thorek, Daniel L. J.; Ulmert, David; Diop, Ndeye-Fatou M.; Lupu, Mihaela E.; Doran, Michael G.; Huang, Ruimin; Abou, Diane S.; Larson, Steven M.; Grimm, Jan

2014-01-01

The invasion status of tumour-draining lymph nodes (LNs) is a critical indicator of cancer stage and is important for treatment planning. Clinicians currently use planar scintigraphy and single-photon emission computed tomography (SPECT) with 99mTc-radiocolloid to guide biopsy and resection of LNs. However, emerging multimodality approaches such as positron emission tomography combined with magnetic resonance imaging (PET/MRI) detect sites of disease with higher sensitivity and accuracy. Here we present a multimodal nanoparticle, 89Zr-ferumoxytol, for the enhanced detection of LNs with PET/MRI. For genuine translational potential, we leverage a clinical iron oxide formulation, altered with minimal modification for radiolabelling. Axillary drainage in naive mice and from healthy and tumour-bearing prostates was investigated. We demonstrate that 89Zr-ferumoxytol can be used for high-resolution tomographic studies of lymphatic drainage in preclinical disease models. This nanoparticle platform has significant translational potential to improve preoperative planning for nodal resection and tumour staging.

Anticancer activity of bacteriophage T4 and its mutant HAP1 in mouse experimental tumour models.

PubMed

Dabrowska, Krystyna; Opolski, Adam; Wietrzyk, Joanna; Switala-Jelen, Kinga; Godlewska, Joanna; Boratynski, Janusz; Syper, Danuta; Weber-Dabrowska, Beata; Gorski, Andrzej

2004-01-01

Previously, we have shown the ability of the bacteriophage T4 and its substrain HAP1 (selected for a higher affinity to melanoma cells) to reveal antimetastatic activity in a mouse melanoma model. Here, we investigated the potential phage anticancer activity in primary tumour models. Mice were inoculated subcutaneously with B16 or LLC cells (collected from in vitro culture). Bacteriophages T4 and HAP1 were injected intraperitoneally daily (8 x 10(8)pfu/mouse, except the experiment concerning the dose-dependence). Treatment with purified preparations of bacteriophage T4 resulted in significant reduction of tumour size, the effect being dose-dependent. HAP1 was more effective than T4 and its activity was also dose-dependent. Parallel experiments with non-purified bacteriophage lysates resulted in significant stimulation of tumour growth. These data suggest that purified bacteriophages may inhibit tumour growth, a phenomenon with potentially important clinical implications in oncology.

Significance of manipulating tumour hypoxia and radiation dose rate in terms of local tumour response and lung metastatic potential, referring to the response of quiescent cell populations

PubMed Central

Masunaga, S; Matsumoto, Y; Kashino, G; Hirayama, R; Liu, Y; Tanaka, H; Sakurai, Y; Suzuki, M; Kinashi, Y; Maruhashi, A; Ono, K

2010-01-01

The purpose of this study was to evaluate the influence of manipulating intratumour oxygenation status and radiation dose rate on local tumour response and lung metastases following radiotherapy, referring to the response of quiescent cell populations within irradiated tumours. B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells. They received γ-ray irradiation at high dose rate (HDR) or reduced dose rate (RDR) following treatment with the acute hypoxia-releasing agent nicotinamide or local hyperthermia at mild temperatures (MTH). Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the quiescent (Q) and total (proliferating + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumour-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. Following HDR irradiation, nicotinamide and MTH enhanced the sensitivity of the total and Q-cell populations, respectively. The decrease in sensitivity at RDR irradiation compared with HDR irradiation was slightly inhibited by MTH, especially in Q cells. Without γ-ray irradiation, nicotinamide treatment tended to reduce the number of lung metastases. With γ-rays, in combination with nicotinamide or MTH, especially the former, HDR irradiation decreased the number of metastases more remarkably than RDR irradiation. Manipulating both tumour hypoxia and irradiation dose rate have the potential to influence lung metastasis. The combination with the acute hypoxia-releasing agent nicotinamide may be more promising in HDR than RDR irradiation in terms of reducing the number of lung metastases. PMID:20739345

A novel synthetic compound exerts effective anti-tumour activity in vivo via the inhibition of tubulin polymerisation in A549 cells.

PubMed

Yan, Jun; Pang, Yanqing; Sheng, Jianfeng; Wang, Yali; Chen, Jie; Hu, Jinhui; Huang, Ling; Li, Xingshu

2015-09-01

Microtubules are critical elements that are involved in a wide range of cellular processes, and thus, they have become an attractive target for many anticancer drugs. A novel synthesised compound, 12P, was identified as new microtubule inhibitor. This compound inhibits tubulin polymerisation through binding to the colchicine-binding site of tubulin. 12P exhibits excellent anti-proliferative activities against a panel of human cancer cell lines, with IC₅₀ values range from 9 to 55nM. Interestingly, compound 12P also displayed equally potent cytotoxicity against several drug-resistant cell lines, and it showed high selectivity for active human umbilical vein endothelial cells (HUVECs). Further flow cytometric analysis showed that 12P induces G₂/M phase arrest and apoptosis in A549 cells. Cellular studies have revealed that the induction of apoptosis by 12P was associated with a collapse of mitochondrial membrane potential (MMP), accumulation of reactive oxygen species (ROS), alterations in the expression of some cell cycle-related proteins (e.g. Cyclin B1, Cdc25c, Cdc2) and some apoptosis-related proteins (e.g. Bax, Bad, Bcl-2, Bcl-xl). Importantly, 12P significantly reduced the growth of xenograft tumours of A549 cells in vivo (tumour inhibitory rate of 12P: 84.2%), without any loss of body weight. Taken together, these in vitro and in vivo results suggested that 12P may become a promising lead compound for the development of new anticancer drugs. Copyright © 2015 Elsevier Inc. All rights reserved.

The tumour suppressor CYLD regulates the p53 DNA damage response

PubMed Central

Fernández-Majada, Vanesa; Welz, Patrick-Simon; Ermolaeva, Maria A.; Schell, Michael; Adam, Alexander; Dietlein, Felix; Komander, David; Büttner, Reinhard; Thomas, Roman K.; Schumacher, Björn; Pasparakis, Manolis

2016-01-01

The tumour suppressor CYLD is a deubiquitinase previously shown to inhibit NF-κB, MAP kinase and Wnt signalling. However, the tumour suppressing mechanisms of CYLD remain poorly understood. Here we show that loss of CYLD catalytic activity causes impaired DNA damage-induced p53 stabilization and activation in epithelial cells and sensitizes mice to chemical carcinogen-induced intestinal and skin tumorigenesis. Mechanistically, CYLD interacts with and deubiquitinates p53 facilitating its stabilization in response to genotoxic stress. Ubiquitin chain-restriction analysis provides evidence that CYLD removes K48 ubiquitin chains from p53 indirectly by cleaving K63 linkages, suggesting that p53 is decorated with complex K48/K63 chains. Moreover, CYLD deficiency also diminishes CEP-1/p53-dependent DNA damage-induced germ cell apoptosis in the nematode Caenorhabditis elegans. Collectively, our results identify CYLD as a deubiquitinase facilitating DNA damage-induced p53 activation and suggest that regulation of p53 responses to genotoxic stress contributes to the tumour suppressor function of CYLD. PMID:27561390

Exercise-induced changes in tumour LDH-B and MCT1 expression are modulated by oestrogen-related receptor alpha in breast cancer-bearing BALB/c mice

PubMed Central

Aveseh, Malihe; Nikooie, Rohollah; Aminaie, Mohsen

2015-01-01

Several factors, including overexpression of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), promote an aerobic lactate production that allows some cancer cells to sustain higher proliferation rates in hostile environments outside the cell. To elucidate the effect of endurance training on the metabolic phenotype of solid tumours, we focused on the tumour expression of LDH-A, LDH-B, MCT1, MCT4, oestrogen-related receptor alpha (ERRα) and LDH isozymes in control (C), trained (T), control+XCT790 (CX) and trained+XCT790 (TX) mice. First, we found that the metabolically altered tumours from the trained animals exhibited lower values for lactate concentration than the control group. The decreased lactate concentration was associated with a shift in the tumour LDH isozyme profile towards LDH-1. These exercise-induced changes were also associated with decreases in the expression of the tumour MCT1, ERRα and CD147 in the trained animals. Secondly, the inhibition of ERRα by treatment of MC4-L2 human breast cancer cells with XCT790 (inverse agonist ligand of ERRα) before injection into the animals not only increased LDH-B expression in the tumour, but also decreased MCT1 expression in the CX group in comparison to the C group. The effects of ERRα inhibition were not additive to the training effects on the expressions of MCT1 and LDH-B in the solid tumours. In conclusion, our results suggest that exercise-induced suppression of ERRα expression modulates alterations in solid tumour expression of LDH-B and MCT1 and contributes towards the prevention of tumour development. PMID:25907793

Chitosan nanoparticle carrying small interfering RNA to platelet-derived growth factor B mRNA inhibits proliferation of smooth muscle cells in rabbit injured arteries.

PubMed

Xia, He; Jun, Ji; Wen-Ping, Ling; Yi-Feng, Pan; Xiao-Ling, Chen

2013-10-01

The purpose of this study was to elucidate the transfection of chitosan nanoparticle carrying small interfering RNA against platelet-derived growth factor B (PDGF-B) to inhibit the expression of PDGF-B mRNA and proliferation of smooth muscle cells. A rabbit iliac artery injury model was constructed. A small interfering RNA (siRNA) against PDGF-B mRNA expression vector was constructed and packaged by chitosan nanoparticle to transfect into the vascular smooth muscle cells (vSMCs) of balloon catheter-injured rabbit iliac artery wall, using a therapeutic ultrasound for the gene delivery. The experiment was divided into two groups: experimental group, denudation and nano-PDGF-B siRNA treated, and only single denudation as control. Effects of the siRNA on the expressions of proliferating cell nuclear antigen (PCNA) and PDGF-B mRNA by vSMCs and the proliferation of vSMCs were observed with the methods of routine pathological, immunohistochemical staining, in situ hybridization and morphometry. The nano siRNA against PDGF-B was successfully transfected. The nano siRNA significantly inhibited the expressions of PCNA and PDGF-B mRNA in intimal vSMCs. The local intimal thickness and area were also reduced remarkably. In conclusion, transfection of chitosan nanoparticle carrying siRNA against PDGF-B mRNA could inhibit proliferation of vSMCs in the rabbit iliac artery injury model. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Comparison of magnetic nanoparticle and microwave hyperthermia cancer treatment methodology and treatment effect in a rodent breast cancer model.

PubMed

Petryk, Alicia A; Giustini, Andrew J; Gottesman, Rachel E; Trembly, B Stuart; Hoopes, P Jack

2013-12-01

The purpose of this study was to compare the efficacy of iron oxide/magnetic nanoparticle hyperthermia (mNPH) and 915 MHz microwave hyperthermia at the same thermal dose in a mouse mammary adenocarcinoma model. A thermal dose equivalent to 60 min at 43 °C (CEM60) was delivered to a syngeneic mouse mammary adenocarcinoma flank tumour (MTGB) via mNPH or locally delivered 915 MHz microwaves. mNPH was generated with ferromagnetic, hydroxyethyl starch-coated magnetic nanoparticles. Following mNP delivery, the mouse/tumour was exposed to an alternating magnetic field (AMF). The microwave hyperthermia treatment was delivered by a 915 MHz microwave surface applicator. Time required for the tumour to reach three times the treatment volume was used as the primary study endpoint. Acute pathological effects of the treatments were determined using conventional histopathological techniques. Locally delivered mNPH resulted in a modest improvement in treatment efficacy as compared to microwave hyperthermia (p = 0.09) when prescribed to the same thermal dose. Tumours treated with mNPH also demonstrated reduced peritumoral normal tissue damage. Our results demonstrate similar tumour treatment efficacy when tumour heating is delivered by locally delivered mNPs and 915 MHz microwaves at the same measured thermal dose. However, mNPH treatments did not result in the same type or level of peritumoral damage seen with the microwave hyperthermia treatments. These data suggest that mNP hyperthermia is capable of improving the therapeutic ratio for locally delivered tumour hyperthermia. These results further indicate that this improvement is due to improved heat localisation in the tumour.

Adapting radiotherapy to hypoxic tumours

NASA Astrophysics Data System (ADS)

Malinen, Eirik; Søvik, Åste; Hristov, Dimitre; Bruland, Øyvind S.; Rune Olsen, Dag

2006-10-01

In the current work, the concepts of biologically adapted radiotherapy of hypoxic tumours in a framework encompassing functional tumour imaging, tumour control predictions, inverse treatment planning and intensity modulated radiotherapy (IMRT) were presented. Dynamic contrast enhanced magnetic resonance imaging (DCEMRI) of a spontaneous sarcoma in the nasal region of a dog was employed. The tracer concentration in the tumour was assumed related to the oxygen tension and compared to Eppendorf histograph measurements. Based on the pO2-related images derived from the MR analysis, the tumour was divided into four compartments by a segmentation procedure. DICOM structure sets for IMRT planning could be derived thereof. In order to display the possible advantages of non-uniform tumour doses, dose redistribution among the four tumour compartments was introduced. The dose redistribution was constrained by keeping the average dose to the tumour equal to a conventional target dose. The compartmental doses yielding optimum tumour control probability (TCP) were used as input in an inverse planning system, where the planning basis was the pO2-related tumour images from the MR analysis. Uniform (conventional) and non-uniform IMRT plans were scored both physically and biologically. The consequences of random and systematic errors in the compartmental images were evaluated. The normalized frequency distributions of the tracer concentration and the pO2 Eppendorf measurements were not significantly different. 28% of the tumour had, according to the MR analysis, pO2 values of less than 5 mm Hg. The optimum TCP following a non-uniform dose prescription was about four times higher than that following a uniform dose prescription. The non-uniform IMRT dose distribution resulting from the inverse planning gave a three times higher TCP than that of the uniform distribution. The TCP and the dose-based plan quality depended on IMRT parameters defined in the inverse planning procedure (fields

Platelet-activating factor receptor (PAF-R)-dependent pathways control tumour growth and tumour response to chemotherapy

PubMed Central

2010-01-01

Background Phagocytosis of apoptotic cells by macrophages induces a suppressor phenotype. Previous data from our group suggested that this occurs via Platelet-activating factor receptor (PAF-R)-mediated pathways. In the present study, we investigated the impact of apoptotic cell inoculation or induction by a chemotherapeutic agent (dacarbazine, DTIC) on tumour growth, microenvironmental parameters and survival, and the effect of treatment with a PAF-R antagonist (WEB2170). These studies were performed in murine tumours: Ehrlich Ascitis Tumour (EAT) and B16F10 melanoma. Methods Tumour growth was assessed by direct counting of EAT cells in the ascitis or by measuring the volume of the solid tumour. Parameters of the tumour microenvironment, such as the frequency of cells expressing cyclo-oxygenase-2 (COX-2), caspase-3 and galectin-3, and microvascular density, were determined by immunohistochemistry. Levels of vascular endothelium growth factor (VEGF) and prostaglandin E2 (PGE2) were determined by ELISA, and levels of nitric oxide (NO) by Griess reaction. PAF-R expression was analysed by immunohistochemistry and flow cytometry. Results Inoculation of apoptotic cells before EAT implantation stimulated tumour growth. This effect was reversed by in vivo pre-treatment with WEB2170. This treatment also reduced tumour growth and modified the microenvironment by reducing PGE2, VEGF and NO production. In B16F10 melanoma, WEB2170 alone or in association with DTIC significantly reduced tumour volume. Survival of the tumour-bearing mice was not affected by WEB2170 treatment but was significantly improved by the combination of DTIC with WEB2170. Tumour microenvironment elements were among the targets of the combination therapy since the relative frequency of COX-2 and galectin-3 positive cells and the microvascular density within the tumour mass were significantly reduced by treatment with WEB2170 or DTIC alone or in combination. Antibodies to PAF-R stained the cells from inside

The in vivo activation of persistent nanophosphors for optical imaging of vascularization, tumours and grafted cells

NASA Astrophysics Data System (ADS)

Maldiney, Thomas; Bessière, Aurélie; Seguin, Johanne; Teston, Eliott; Sharma, Suchinder K.; Viana, Bruno; Bos, Adrie J. J.; Dorenbos, Pieter; Bessodes, Michel; Gourier, Didier; Scherman, Daniel; Richard, Cyrille

2014-04-01

Optical imaging for biological applications requires more sensitive tools. Near-infrared persistent luminescence nanoparticles enable highly sensitive in vivo optical detection and complete avoidance of tissue autofluorescence. However, the actual generation of persistent luminescence nanoparticles necessitates ex vivo activation before systemic administration, which prevents long-term imaging in living animals. Here, we introduce a new generation of optical nanoprobes, based on chromium-doped zinc gallate, whose persistent luminescence can be activated in vivo through living tissues using highly penetrating low-energy red photons. Surface functionalization of this photonic probe can be adjusted to favour multiple biomedical applications such as tumour targeting. Notably, we show that cells can endocytose these nanoparticles in vitro and that, after intravenous injection, we can track labelled cells in vivo and follow their biodistribution by a simple whole animal optical detection, opening new perspectives for cell therapy research and for a variety of diagnosis applications.

Reducing Tumour Hypoxia via Oral Administration of Oxygen Nanobubbles

PubMed Central

Owen, Joshua; McEwan, Conor; Nesbitt, Heather; Bovornchutichai, Phurit; Averre, Raymond; Borden, Mark; McHale, Anthony P.; Callan, John F.

2016-01-01

Hypoxia has been shown to be a key factor inhibiting the successful treatment of solid tumours. Existing strategies for reducing hypoxia, however, have shown limited efficacy and/or adverse side effects. The aim of this study was to investigate the potential for reducing tumour hypoxia using an orally delivered suspension of surfactant-stabilised oxygen nanobubbles. Experiments were carried out in a mouse xenograft tumour model for human pancreatic cancer (BxPc-3 cells in male SCID mice). A single dose of 100 μL of oxygen saturated water, oxygen nanobubbles or argon nanobubbles was administered via gavage. Animals were sacrificed 30 minutes post-treatment (3 per group) and expression of hypoxia-inducible-factor-1α (HIF1α) protein measured by real time quantitative polymerase chain reaction and Western blot analysis of the excised tumour tissue. Neither the oxygen saturated water nor argon nanobubbles produced a statistically significant change in HIF1α expression at the transcriptional level. In contrast, a reduction of 75% and 25% in the transcriptional and translational expression of HIF1α respectively (p<0.001) was found for the animals receiving the oxygen nanobubbles. This magnitude of reduction has been shown in previous studies to be commensurate with an improvement in outcome with both radiation and drug-based treatments. In addition, there was a significant reduction in the expression of vascular endothelial growth factor (VEGF) in this group and corresponding increase in the expression of arrest-defective protein 1 homolog A (ARD1A). PMID:28036332

Reducing Tumour Hypoxia via Oral Administration of Oxygen Nanobubbles.

PubMed

Owen, Joshua; McEwan, Conor; Nesbitt, Heather; Bovornchutichai, Phurit; Averre, Raymond; Borden, Mark; McHale, Anthony P; Callan, John F; Stride, Eleanor

2016-01-01

Hypoxia has been shown to be a key factor inhibiting the successful treatment of solid tumours. Existing strategies for reducing hypoxia, however, have shown limited efficacy and/or adverse side effects. The aim of this study was to investigate the potential for reducing tumour hypoxia using an orally delivered suspension of surfactant-stabilised oxygen nanobubbles. Experiments were carried out in a mouse xenograft tumour model for human pancreatic cancer (BxPc-3 cells in male SCID mice). A single dose of 100 μL of oxygen saturated water, oxygen nanobubbles or argon nanobubbles was administered via gavage. Animals were sacrificed 30 minutes post-treatment (3 per group) and expression of hypoxia-inducible-factor-1α (HIF1α) protein measured by real time quantitative polymerase chain reaction and Western blot analysis of the excised tumour tissue. Neither the oxygen saturated water nor argon nanobubbles produced a statistically significant change in HIF1α expression at the transcriptional level. In contrast, a reduction of 75% and 25% in the transcriptional and translational expression of HIF1α respectively (p<0.001) was found for the animals receiving the oxygen nanobubbles. This magnitude of reduction has been shown in previous studies to be commensurate with an improvement in outcome with both radiation and drug-based treatments. In addition, there was a significant reduction in the expression of vascular endothelial growth factor (VEGF) in this group and corresponding increase in the expression of arrest-defective protein 1 homolog A (ARD1A).

[Surgical Management of Peritoneal Surface Malignancy with Respect to Tumour Type, Tumour Stage and Individual Tumour Biology].

PubMed

Beckert, S; Struller, F; Grischke, E-M; Glatzle, J; Zieker, D; Königsrainer, A; Königsrainer, I

2016-08-01

Peritoneal tumour dissemination is still considered as a terminal disease. For the last two decades, cytoreductive surgery (CRS) combined with intraoperative hyperthermic chemotherapy (HIPEC) has been popularised by Paul Sugarbaker almost doubling survival in selected patients compared with systemic chemotherapy alone. Nowadays, this particular treatment protocol is available in comprehensive cancer centres with reasonable mortality and morbidity. However, patient selection is still challenging. In general, CRS and HIPEC is indicated in primary peritoneal tumours such as mesothelioma and pseudomyxoma peritonei as well as in peritoneal metastases derived from gastrointestinal malignancies and ovarian cancers. Since systemic tumour spread is uncommon in patients with peritoneal metastases, peritoneal tumour dissemination was defined as localised disease within the "compartment abdomen". However, CRS and HIPEC are only beneficial as long as complete cytoreduction is achieved (CC-0 or CC-1). Histopathological parameters, the Sugarbaker peritoneal carcinomatosis index (PCI) and general condition of the patient have been established as patient selection criteria. In primary peritoneal cancers, individual tumour biology is the predominant criterium for patient selection as opposed to intraabdominal tumour load in peritoneal metastases derived from gastrointestinal cancers. In gastric cancer, CRS and HIPEC should be restricted to synchronous limited disease because of its biological aggressiveness. In patients with free floating cancer cells without macroscopic signs of peritoneal spread, however, CRS and HIPEC following preoperative "neoadjuvant" chemotherapy preserves chances for cure. So far, there is no general recommendation for CRS and HIPEC by clinical practice guidelines. In the recent S3 guideline for treatment of colorectal cancer, however, CRS and HIPEC have been included as possible treatment options. Georg Thieme Verlag KG Stuttgart · New York.

Exercise-induced changes in tumour LDH-B and MCT1 expression are modulated by oestrogen-related receptor alpha in breast cancer-bearing BALB/c mice.

PubMed

Aveseh, Malihe; Nikooie, Rohollah; Aminaie, Mohsen

2015-06-15

Monocarboxylate transporters (MCTs) and lactate dehydrogenase A (LDH-A) play important roles in sustaining the glycolytic phenotype seen in cancer. Endurance training improves aerobic capacity; however, whether endurance training alters the metabolic phenotype of a solid tumour, from the perspective of lactate metabolism, is yet to be proven. This study showed that endurance training decreases expression of the MCT1 basigin (CD147) and LDH-A , and also increases LDH-B expression in solid tumours and attenuates tumour lactate metabolism. Similar results for MCT1 and LDH-B were found with inhibition of the oestrogen-related receptor alpha (ERRα). The training effects were not additive to the ERRα effects on MCT1 and LDH-B expression in the tumour, which indicated that exercise-induced alterations in MCT1 and LDH-B expression were modulated by ERRα. These results suggest that endurance training could be a useful tool in cancer therapy, especially in basal-like and luminal-like breast carcinomas. Several factors, including overexpression of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), promote an aerobic lactate production that allows some cancer cells to sustain higher proliferation rates in hostile environments outside the cell. To elucidate the effect of endurance training on the metabolic phenotype of solid tumours, we focused on the tumour expression of LDH-A, LDH-B, MCT1, MCT4, oestrogen-related receptor alpha (ERRα) and LDH isozymes in control (C), trained (T), control+XCT790 (CX) and trained+XCT790 (TX) mice. First, we found that the metabolically altered tumours from the trained animals exhibited lower values for lactate concentration than the control group. The decreased lactate concentration was associated with a shift in the tumour LDH isozyme profile towards LDH-1. These exercise-induced changes were also associated with decreases in the expression of the tumour MCT1, ERRα and CD147 in the trained animals. Secondly, the

Expression of epidermal growth factor receptor and vascular endothelial growth factor in malignant canine epithelial nasal tumours.

PubMed

Shiomitsu, K; Johnson, C L; Malarkey, D E; Pruitt, A F; Thrall, D E

2009-06-01

Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) signalling pathways play a role in carcinogenesis. Inhibition of EGF receptor (EGFR) and of VEGF is effective in increasing the radiation responsiveness of neoplastic cells both in vitro and in human trials. In this study, immunohistochemical evaluation was employed to determine and characterize the potential protein expression levels and patterns of EGFR and VEGF in a variety of canine malignant epithelial nasal tumours. Of 24 malignant canine nasal tumours, 13 (54.2%) were positive for EGFR staining and 22 (91.7%) were positive for VEGF staining. The intensity and percentage of immunohistochemically positive neoplastic cells for EGFR varied. These findings indicate that EGFR and VEGF proteins were present in some malignant epithelial nasal tumours in the dogs, and therefore, it may be beneficial to treat canine patients with tumours that overexpress EGFR and VEGF with specific inhibitors in conjunction with radiation.

New thermosensitive nanoparticles prepared by biocompatible pegylated aliphatic polyester block copolymers for local cancer treatment.

PubMed

Karavelidis, Vassilios; Bikiaris, Dimitrios; Avgoustakis, Konstantinos

2015-02-01

New pegylated thermosensitive polymers were developed to study them as drug vehicles in targeting release nanoparticulate systems of anticancer drugs. The drug vehicles were prepared in the form of core-shell nanoparticles using novel polymeric materials synthesized by copolymerization of poly(propylene adipate) (PPAd) and methoxy-polyethylene glycol (mPEG) with different molecular weights. The physical and chemical properties of the synthesized mPEG-PPAd copolymers were studied using several techniques, and their cytocompatibility was evaluated. For drug nanoencapsulation, a water in oil (W/O) emulsification and solvent evaporation technique was used and the prepared nanoparticles were studied for their physical properties, morphology, drug release and anticancer efficacy against cancer cell lines. The size of the nanoparticles lied in a range suitable for tumour targeting. Drug release was affected by the composition of polymer, the temperature and pH of the release medium. The release results obtained indicate that judicious selection of nanoparticles composition may allow for enhanced drug delivery to the tumours following application of local hyperthermia. The paclitaxel-loaded mPEG-PPAd nanoparticles were found to be cytotoxic against to the human hepatoma HepG2) and the human epithelial (HeLa) cancer cell lines. Enhanced cytotoxicity against the HeLa cells was observed at elevated temperature (42°C compared with 37°C), providing support for the potential usefulness of the mPEG-PPAd nanoparticles for the development of thermo-sensitive anticancer drug delivery systems. © 2014 Royal Pharmaceutical Society.

Magnetic nanoparticles for selective heating of magnetically labelled cells in culture: preliminary investigation

NASA Astrophysics Data System (ADS)

Hilger, Ingrid; Kießling, Andreas; Romanus, Erik; Hiergeist, Robert; Hergt, Rudolf; Andrä, Wilfried; Roskos, Martin; Linss, Werner; Weber, Peter; Weitschies, Werner; Kaiser, Werner A.

2004-08-01

The minimally invasive elimination of tumours using heating as a therapeutic agent is an emerging technology in medical applications. Particularly, the intratumoural application of magnetic nanoparticles as potential heating sources when exposed to an alternating magnetic field has been demonstrated. The present work deals with the estimation of the basic relationships when the magnetic material has access and binds to structures on cell membranes of target cells at the tumour region, particularly as a consequence of administration through tumour supplying vessels. Therefore, using mouse endothelial cells in culture, the binding of dextran coated magnetic nanoparticles (mean hydrodynamic particle diameter 65 nm) was modelled using the periodate method. The efficacy of cell labelling was demonstrated by magnetorelaxometry (MRX)—a selective method for the detection of only those magnetic nanoparticles that were immobilized—as well as by electron microscopy and iron staining. The amount of iron immobilized on cells was found to be 153 ± 56 µg Fe per 1 × 107 cells as determined by atomic absorption spectrometry. Moreover, after exposure of those 1 × 107 labelled cells to an alternating magnetic field (frequency 410 kHz, amplitude 11 kA m-1) for 5 min, temperature increases of 2 °C were achieved. The consequences of particle immobilization are reflected by the results of the measurements related to the specific heating power (SHP) of the magnetic material. Basically, the heating potential is explained by the superposition of Brown and Neél relaxation while for immobilized nanoparticles the Brown contribution is absent. In the long term the data could open the door to targeted magnetic heating after further optimization of the heating potential of magnetic material as well as after functionalization with biomolecules which recognize specific structures on the surface of cells at the target region.

The biotoxicity of hydroxyapatite nanoparticles to the plant growth.

PubMed

Jiang, Hao; Liu, Jin-Ku; Wang, Jian-Dong; Lu, Yi; Zhang, Min; Yang, Xiao-Hong; Hong, Dan-Jing

2014-04-15

In the present study, hydroxyapatite (HAP) nanoparticles of different particle sizes with high crystallinity and similiar structure were prepared by hydrothermal method. The crystal structure and particle size were characterized by X-ray diffraction pattern (XRD), transmission electron microscopy (TEM) and Fourier transform infrared (FT-IR) spectroscopy. Mung bean sprouts were first used as experimental models. Instead of by MTT assay, the cytoxicity of HAP nanoparticles were proved and evaluated by measuring the hypocotyle length of mung bean sprouts in the culture media. The result showed that the inhibition effect to the growth of mung bean sprouts enhanced when HAP nanoparticles existed. Culture media of HAP nanoparticles with different concentrations and particle sizes was prepared to investigate the level of inhibition effect to the growth of mung bean sprouts. The result found that hypocotyl length of mung bean sprouts were the shortest cultured in 5mg/mL culture media in which the HAP nanoparticles were prepared by hydrothermal method for 24h. It was concluded the inhibition effect depended on the amount of intracellular HAP nanoparticles. The nanostructure and Ca(2+) concentration were considered as the main factors to cause cell apoptosis which was the reason of inhibition. The study provided a preliminary perspective about biotoxicity of HAP nanomaterials to the plant growth. Copyright © 2014 Elsevier B.V. All rights reserved.

Dual antiplatelet therapy with clopidogrel and aspirin increases mortality in 4T1 metastatic breast cancer-bearing mice by inducing vascular mimicry in primary tumour

PubMed Central

Smeda, Marta; Kieronska, Anna; Proniewski, Bartosz; Jasztal, Agnieszka; Selmi, Anna; Wandzel, Krystyna; Zakrzewska, Agnieszka; Wojcik, Tomasz; Przyborowski, Kamil; Derszniak, Katarzyna; Stojak, Marta; Kaczor, Dawid; Buczek, Elzbieta; Watala, Cezary; Wietrzyk, Joanna; Chlopicki, Stefan

2018-01-01

Platelet inhibition has been considered an effective strategy for combating cancer metastasis and compromising disease malignancy although recent clinical data provided evidence that long-term platelet inhibition might increase incidence of cancer deaths in initially cancer-free patients. In the present study we demonstrated that dual anti-platelet therapy based on aspirin and clopidogrel (ASA+Cl), a routine regiment in cardiovascular patients, when given to cancer-bearing mice injected orthotopically with 4T1 breast cancer cells, promoted progression of the disease and reduced mice survival in association with induction of vascular mimicry (VM) in primary tumour. In contrast, treatment with ASA+Cl or platelet depletion did reduce pulmonary metastasis in mice, if 4T1 cells were injected intravenously. In conclusion, distinct platelet-dependent mechanisms inhibited by ASA+Cl treatment promoted cancer malignancy and VM in the presence of primary tumour and afforded protection against pulmonary metastasis in the absence of primary tumour. In view of our data, long-term inhibition of platelet function by dual anti-platelet therapy (ASA+Cl) might pose a hazard when applied to a patient with undiagnosed and untreated malignant cancer prone to undergo VM. PMID:29707148

Infective complications following tumour endoprosthesis surgery for bone and soft tissue tumours.

PubMed

Peel, T; May, D; Buising, K; Thursky, K; Slavin, M; Choong, P

2014-09-01

This study aims to describe the incidence of infective complications, including tumour endoprosthesis infection, in a cohort of patients undergoing tumour endoprosthesis surgery in Victoria, Australia. This retrospective cohort study was performed over 15 years (January 1996-December 2010). 121 patients underwent tumour endoprosthesis surgery during the study period. Patients were followed for a median of 34 months (interquartile range [IQR] 17, 80). Overall, 34 patients (28%) experienced infective complications including: bacteraemia in 19 patients (16%) and tumour endoprosthesis infection in 17 (14%). The majority of patients with early and late acute infections (haematogenous) were managed with debridement and retention of the prosthesis in addition to biofilm-active antibiotics. Late chronic infections were predominantly managed by exchange of the prosthesis. The overall success rate of treatment was 71%. The success rate for debridement and retention was 75% compared with 67% for exchange procedures. There is a significant rate of infective complications following tumour endoprosthesis surgery including 14% of patients experiencing infection involving the tumour endoprosthesis. This study is the first to report on outcomes from debridement and retention of the prosthesis; which had comparable success rates to other treatment modalities. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Re-programming tumour cell metabolism to treat cancer: no lone target for lonidamine.

PubMed

Bhutia, Yangzom D; Babu, Ellappan; Ganapathy, Vadivel

2016-06-01

Tumour cell metabolism is very different from normal cell metabolism; cancer cells re-programme the metabolic pathways that occur in normal cells in such a manner that it optimizes their proliferation, growth and survival. Although this metabolic re-programming obviously operates to the advantage of the tumour, it also offers unique opportunities for effective cancer therapy. Molecules that target the tumour cell-specific metabolic pathways have potential as novel anti-cancer drugs. Lonidamine belongs to this group of molecules and is already in use in some countries for cancer treatment. It has been known for a long time that lonidamine interferes with energy production in tumour cells by inhibiting hexokinase II (HKII), a glycolytic enzyme. However, subsequent studies have uncovered additional pharmacological targets for the drug, which include the electron transport chain and the mitochondrial permeability transition pore, thus expanding the pharmacological effects of the drug on tumour cell metabolism. A study by Nancolas et al. in a recent issue of the Biochemical Journal identifies two additional new targets for lonidamine: the pyruvate transporter in the mitochondria and the H(+)-coupled monocarboxylate transporters in the plasma membrane (PM). It is thus becoming increasingly apparent that the anti-cancer effects of lonidamine do not occur through a single target; the drug works at multiple sites. Irrespective of the molecular targets, what lonidamine does in the end is to undo what the tumour cells have done in terms of re-programming cellular metabolism and mitochondrial function. © 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

[Neonatal tumours and congenital malformations].

PubMed

Berbel Tornero, O; Ortega García, J A; Ferrís i Tortajada, J; García Castell, J; Donat i Colomer, J; Soldin, O P; Fuster Soler, J L

2008-06-01

The association between pediatric cancer and congenital abnormalities is well known but, there is no exclusive data on the neonatal period and the underlying etiopathogenic mechanisms are unknown. First, to analyze the frequency of neonatal tumours associated with congenital abnormalities; and second, to comment on the likely etiopathogenic hypotheses of a relationship between neonatal tumours and congenital abnormalities. Historical series of neonatal tumours from La Fe University Children's Hospital in Valencia (Spain), from January 1990 to December 1999. Histological varieties of neonatal tumours and associated congenital abnormalities were described. A systematic review of the last 25 years was carried out using Medline, Cancerlit, Index Citation Science and Embase. The search profile used was the combination of "neonatal/congenital-tumors/cancer/neoplasms" and "congenital malformations/birth defects". 72 neonatal tumours were identified (2.8% of all pediatric cancers diagnosed in our hospital) and in 15 cases (20.8%) there was some associated malformation, disease or syndrome. The association between congenital abnormalities and neonatal tumours were: a) angiomas in three patients: two patients with congenital heart disease with a choanal stenosis, laryngomalacia; b) neuroblastomas in two patients: horseshoe kidney with vertebral anomalies and other with congenital heart disease; c) teratomas in two patients: one with cleft palate with vertebral anomalies and other with metatarsal varus; d) one tumour of the central nervous system with Bochdaleck hernia; e) heart tumours in four patients with tuberous sclerosis; f) acute leukaemia in one patient with Down syndrome and congenital heart disease; g) kidney tumour in one case with triventricular hydrocephaly, and h) adrenocortical tumour: hemihypertrophy. The publications included the tumours diagnosed in different pediatric periods and without unified criteria to classify the congenital abnormalities. Little data

Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation.

PubMed

Papaspyridonos, Marianna; Matei, Irina; Huang, Yujie; do Rosario Andre, Maria; Brazier-Mitouart, Helene; Waite, Janelle C; Chan, April S; Kalter, Julie; Ramos, Ilyssa; Wu, Qi; Williams, Caitlin; Wolchok, Jedd D; Chapman, Paul B; Peinado, Hector; Anandasabapathy, Niroshana; Ocean, Allyson J; Kaplan, Rosandra N; Greenfield, Jeffrey P; Bromberg, Jacqueline; Skokos, Dimitris; Lyden, David

2015-04-29

A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive 'macroenvironment' mediated in part through tumour-secreted factors. Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFβ, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression. Genetic inactivation of Id1 largely corrects the myeloid imbalance, whereas Id1 overexpression in the absence of tumour-derived factors re-creates it. Id1 overexpression leads to systemic immunosuppression by downregulation of key molecules involved in DC differentiation and suppression of CD8 T-cell proliferation, thus promoting primary tumour growth and metastatic progression. Furthermore, advanced melanoma patients have increased plasma TGFβ levels and express higher levels of ID1 in myeloid peripheral blood cells. This study reveals a critical role for Id1 in suppressing the anti-tumour immune response during tumour progression and metastasis.

Cyclodextrin-Modified Porous Silicon Nanoparticles for Efficient Sustained Drug Delivery and Proliferation Inhibition of Breast Cancer Cells.

PubMed

Correia, Alexandra; Shahbazi, Mohammad-Ali; Mäkilä, Ermei; Almeida, Sérgio; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A

2015-10-21

Over the past decade, the potential of polymeric structures has been investigated to overcome many limitations related to nanosized drug carriers by modulating their toxicity, cellular interactions, stability, and drug-release kinetics. In this study, we have developed a successful nanocomposite consisting of undecylenic acid modified thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs) loaded with an anticancer drug, sorafenib, and surface-conjugated with heptakis(6-amino-6-deoxy)-β-cyclodextrin (HABCD) to show the impact of the surface polymeric functionalization on the physical and biological properties of the drug-loaded nanoparticles. Cytocompatibility studies showed that the UnTHCPSi-HABCD NPs were not toxic to breast cancer cells. HABCD also enhanced the suspensibility and both the colloidal and plasma stabilities of the UnTHCPSi NPs. UnTHCPSi-HABCD NPs showed a significantly increased interaction with breast cancer cells compared to bare NPs and also sustained the drug release. Furthermore, the sorafenib-loaded UnTHCPSi-HABCD NPs efficiently inhibited cell proliferation of the breast cancer cells.

Colorimetric assay of heparin in plasma based on the inhibition of oxidase-like activity of citrate-capped platinum nanoparticles.

PubMed

You, Jyun-Guo; Liu, Yao-Wen; Lu, Chi-Yu; Tseng, Wei-Lung; Yu, Cheng-Ju

2017-06-15

We report citrate-capped platinum nanoparticles (Pt NPs) as oxidase mimetics for effectively catalyzing the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB), 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid), dopamine, and methylene blue in the presence of O 2 . To confirm oxidase-like activity of citrate-capped Pt NPs, their activity toward oxygen reduction reaction was studied using cyclic voltammetry and rotating ring-disk electrode method. The results obtained showed that Pt NP NPs can catalyze the oxidation of organic substrates to the colored product and the reduction of oxygen to water through a four-electron exchange process. Because the aggregation of Pt NPs can inhibit their oxidase-like activity and protamine can recognize heparin, we prepared the protamine-modified Pt NPs through direct adsorption on the surface of citrate-capped Pt NPs. The electrostatic attraction between heparin and protamine-stabilized Pt NPs induced nanoparticle aggregation, inhibiting their catalytic activity. Therefore, the lowest detectable heparin concentrations through UV-vis absorption and by the naked eye were estimated to be 0.3 and 60nM, respectively. Moreover, the proposed system enabled the determination of the therapeutic heparin concentration in a single drop of blood. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparative toxicity of copper nanoparticles across three Lemnaceae species.

PubMed

Song, Lan; Vijver, Martina G; Peijnenburg, Willie J G M

2015-06-15

Metallic nanoparticles can end up in aquatic ecosystems due to their widespread application. Even though the toxicological effects of metallic nanoparticles to a diversity of species have been reported extensively, the toxicological data achieved in different studies are not always comparable and little is known regarding the comparative toxicity of nanoparticles across species, as different test strategies and endpoints were applied. To attempt to fill this knowledge gap, Spirodela polyrhiza, Lemna minor and Wolffia arrhiza were exposed to 25 nm spherical copper nanoparticles to investigate the inhibiting effect of copper nanoparticle suspensions across species at three endpoints: total frond area, frond number and dry weight based relative growth rate. The total frond area based relative growth rate was found to be the most sensitive endpoint, with an EC50 of 1.15±0.09 mg/L for S. polyrhiza, 0.84±0.12 mg/L for L. minor and 0.64±0.05 mg/L for W. arrhiza. Both the particles and the copper ions contributed to the inhibiting effects of copper nanoparticle suspensions at all endpoints studied. Dose-response related inhibiting effects caused by the copper ions were found at all endpoints studied, whereas the particles only showed dose-response related inhibiting effects on the total frond area based relative growth rate. This suggests that different physiological processes are involved in case of exposure to particles and copper ions. W. arrhiza was found to be the most sensitive species tested and S. polyrhiza was the least sensitive species tested, when the inhibiting effect was evaluated based on the relative growth rate calculated from total frond area. These findings exemplify the importance of identifying the suitable endpoints of toxicity assessment and considering the intrinsic differences between species when evaluating the toxicological profile of metallic nanoparticles across species. Copyright © 2015 Elsevier B.V. All rights reserved.

Climacostol reduces tumour progression in a mouse model of melanoma via the p53-dependent intrinsic apoptotic programme

PubMed Central

Perrotta, Cristiana; Buonanno, Federico; Zecchini, Silvia; Giavazzi, Alessio; Proietti Serafini, Francesca; Catalani, Elisabetta; Guerra, Laura; Belardinelli, Maria Cristina; Picchietti, Simona; Fausto, Anna Maria; Giorgi, Simone; Marcantoni, Enrico; Clementi, Emilio; Ortenzi, Claudio; Cervia, Davide

2016-01-01

Climacostol, a compound produced by the ciliated protozoan Climacostomum virens, displayed cytotoxic properties in vitro. This study demonstrates that it has anti-tumour potential. Climacostol caused a reduction of viability/proliferation of B16-F10 mouse melanoma cells, a rapidly occurring DNA damage, and induced the intrinsic apoptotic pathway characterised by the dissipation of the mitochondrial membrane potential, the translocation of Bax to the mitochondria, the release of Cytochrome c from the mitochondria, and the activation of Caspase 9-dependent cleavage of Caspase 3. The apoptotic mechanism of climacostol was found to rely on the up-regulation of p53 and its targets Noxa and Puma. In vivo analysis of B16-F10 allografts revealed a persistent inhibition of tumour growth rate when melanomas were treated with intra-tumoural injections of climacostol. In addition, it significantly improved the survival of transplanted mice, decreased tumour weight, induced a remarkable reduction of viable cells inside the tumour, activated apoptosis and up-regulated the p53 signalling network. Importantly, climacostol toxicity was more selective against tumour than non-tumour cells. The anti-tumour properties of climacostol and the molecular events associated with its action indicate that it is a powerful agent that may be considered for the design of pro-apoptotic drugs for melanoma therapy. PMID:27271364

Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas.

PubMed

Yoon, C; Lee, H-J; Park, D J; Lee, Y-J; Tap, W D; Eisinger-Mathason, T S K; Hart, C P; Choy, E; Simon, M C; Yoon, S S

2015-06-30

Human sarcomas with a poor response to vascular endothelial growth factor-A (VEGF-A) inhibition and radiation therapy (RT) have upregulation of hypoxia-inducible factor 1α (HIF-1α) and HIF-1α target genes. This study examines the addition of the hypoxia-activated chemotherapy TH-302 to VEGF-A inhibition and RT (a.k.a. trimodality therapy). Trimodality therapy was examined in two xenograft models and in vitro in tumour endothelial cells and sarcoma cell lines. In both mouse models, VEGF-A inhibition and radiation showed greater efficacy than either therapy alone in slowing sarcoma growth. When TH-302 was added, this trimodality therapy completely blocked tumour growth with tumours remaining dormant for over 3 months after cessation of therapy. Trimodality therapy caused 2.6- to 6.2-fold more endothelial cell-specific apoptosis than bimodality therapies, and microvessel density and HIF-1α activity were reduced to 11-13% and 13-20% of control, respectively. When trimodality therapy was examined in vitro, increases in DNA damage and apoptosis were much more pronounced in tumour endothelial cells compared with that in sarcoma cells, especially under hypoxia. The combination of TH-302, VEGF-A inhibition, and RT is highly effective in preclinical models of sarcoma and is associated with increased DNA damage and apoptosis in endothelial cells and decreased HIF-1α activity.

[Why are carotid glomus tumours dangerous?].

PubMed

Certík, B; Třeška, V

2014-10-01

Carotid body tumours are rare, usually benign tumours. The dangerous nature of carotid body tumours is due to their hypervascularization and the intimate relationship to cervical arteries and cranial nerves. In a case report, the authors document that misdiagnosis and efforts to remove or obtain a biopsy of the tumour outside vascular centres can be more dangerous for the patient than the nature of the tumour itself.

Quantum dots and nanoparticles for photodynamic and radiation therapies of cancer

PubMed Central

Juzenas, Petras; Chen, Wei; Sun, Ya-Ping; Coelho, Manuel Alvaro Neto; Generalov, Roman; Generalova, Natalia; Christensen, Ingeborg Lie

2009-01-01

Semiconductor quantum dots and nanoparticles composed of metals, lipids or polymers have emerged with promising applications for early detection and therapy of cancer. Quantum dots with unique optical properties are commonly composed of cadmium contained semiconductors. Cadmium is potentially hazardous, and toxicity of such quantum dots to living cells, and humans, is not yet systematically investigated. Therefore, search for less toxic materials with similar targeting and optical properties is of further interest. Whereas, the investigation of luminescence nanoparticles as light sources for cancer therapy is very interesting. Despite advances in neurosurgery and radiotherapy the prognosis for patients with malignant gliomas has changed little for the last decades. Cancer treatment requires high accuracy in delivering ionizing radiation to reduce toxicity to surrounding tissues. Recently some research has been focused in developing photosensitizing quantum dots for production of radicals upon absorption of visible light. In spite of the fact that visible light is safe, this approach is suitable to treat only superficial tumours. Ionizing radiation (X-rays and gamma rays) penetrate much deeper thus offering a big advantage in treating patients with tumours in internal organs. Such concept of using quantum dots and nanoparticles to yield electrons and radicals in photodynamic and radiation therapies as well their combination is reviewed in this article. PMID:18840487

Treatment with phosphotidylglycerol-based nanoparticles prevents motor deficits induced by proteasome inhibition: implications for Parkinson's disease.

PubMed

Fitzgerald, Patrick; Mandel, Arkady; Bolton, Anthony E; Sullivan, Aideen M; Nolan, Yvonne

2008-12-22

Failure of the ubiquitin-proteasome system to degrade abnormal proteins may underlie the accumulation of alpha-synuclein and dopaminergic neuronal degeneration that occurs in Parkinson's disease. Consequently, a reduction of functional proteasome activity has been implicated in Parkinson's disease. VP025 (Vasogen Inc.) is a preparation of phospholipid nanoparticles incorporating phosphatidylglycerol that has been shown to have neuroprotective effects. We show that VP025 prevents the deficits in motor coordination and dopamine observed in a proteasome inhibitor rat model of PD. Thus, VP025 may have a therapeutic effect on the impairment of dopaminergic-mediated motor activity induced by proteasome inhibition.

Photodynamic therapy augments the efficacy of oncolytic vaccinia virus against primary and metastatic tumours in mice

PubMed Central

Gil, M; Bieniasz, M; Seshadri, M; Fisher, D; Ciesielski, M J; Chen, Y; Pandey, R K; Kozbor, D

2011-01-01

Background: Therapies targeted towards the tumour vasculature can be exploited for the purpose of improving the systemic delivery of oncolytic viruses to tumours. Photodynamic therapy (PDT) is a clinically approved treatment for cancer that is known to induce potent effects on tumour vasculature. In this study, we examined the activity of PDT in combination with oncolytic vaccinia virus (OVV) against primary and metastatic tumours in mice. Methods: The effect of 2-[1-hexyloxyethyl-]-2-devinyl pyropheophorbide-a (HPPH)-sensitised-PDT on the efficacy of oncolytic virotherapy was investigated against subcutaneously implanted syngeneic murine NXS2 neuroblastoma and human FaDu head and neck squamous cell carcinoma xenografts in nude mice. Treatment efficacy was evaluated by monitoring tumour growth and survival. The effects of combination treatment on vascular function were examined using magnetic resonance imaging (MRI) and immunohistochemistry, whereas viral replication in tumour cells was analysed by a standard plaque assay. Normal tissue phototoxicity following PDT-OV treatment was studied using the mouse foot response assay. Results: Combination of PDT with OVV resulted in inhibition of primary and metastatic tumour growth compared with either monotherapy. PDT-induced vascular disruption resulted in higher intratumoural viral titres compared with the untreated tumours. Five days after delivery of OVV, there was a loss of blood flow to the interior of tumour that was associated with infiltration of neutrophils. Administration of OVV did not result in any additional photodynamic damage to normal mouse foot tissue. Conclusion: These results provide evidence into the usefulness of PDT as a means of enhancing intratumoural replication and therapeutic efficacy of OV. PMID:21989183

Extract of corn silk (stigma of Zea mays) inhibits the tumour necrosis factor-alpha- and bacterial lipopolysaccharide-induced cell adhesion and ICAM-1 expression.

PubMed

Habtemariam, S

1998-05-01

Treatment of human endothelial cells with cytokines such as tumour necrosis factor-alpha (TNF) or E. coli lipopolysaccharide (LPS) induces the expression of several adhesion molecules and enhances leukocyte adhesion to endothelial cell surface. Interfering with this leukocyte adhesion or adhesion molecules upregulation is an important therapeutic target for the treatment of bacterial sepsis and various inflammatory diseases. In the course of screening marketed European anti-inflammatory herbal drugs for TNF antagonistic activity, a crude ethanolic extract of corn silk (stigma of Zea mays) exhibited significant activity. The extract at concentrations of 9-250 micrograms/ml effectively inhibited the TNF- and LPS-induced adhesiveness of EAhy 926 endothelial cells to monocytic U937 cells. Similar concentration ranges of corn silk extract did also block the TNF and LPS but not the phorbol 12-myristate 13-acetate-induced ICAM-1 expression on EAhy 926 endothelial cell surface. The extract did not alter the production of TNF by LPS-activated macrophages and failed to inhibit the cytotoxic activity of TNF. It is concluded that corn silk possesses important therapeutic potential for TNF- and LPS-mediated leukocyte adhesion and trafficking.

Tumours of bones and joints

PubMed Central

Misdorp, W.; Van Der Heul, R. O.

1976-01-01

Tumours of bones and joints are not infrequent in dogs but are rare in other domestic animals. In the dog, most bone tumours are malignant; osteosarcomas are by far the most frequently encountered tumours, especially in giant breeds and boxers. The following main categories of bone tumour are described: bone-forming, cartilage-forming, giant cell, marrow, vascular, miscellaneous, metastatic, unclassified, and tumour-like lesions. The tumours of joints and related structures are classified as synovial sarcomas, fibroxanthomas, and malignant giant cell tumour of soft tissues. ImagesFig. 21Fig. 22Fig. 23Fig. 24Fig. 17Fig. 18Fig. 19Fig. 20Fig. 29Fig. 30Fig. 31Fig. 32Fig. 33Fig. 34Fig. 35Fig. 36Fig. 25Fig. 26Fig. 27Fig. 28Fig. 1Fig. 2Fig. 3Fig. 4Fig. 37Fig. 38Fig. 39Fig. 40Fig. 5Fig. 6Fig. 7Fig. 8Fig. 13Fig. 14Fig. 15Fig. 16Fig. 9Fig. 10Fig. 11Fig. 12 PMID:1086157

Inhibitory effects of CP on the growth of human gastric adenocarcinoma BGC-823 tumours in nude mice.

PubMed

Wang, Hai-Jun; Liu, Yu; Zhou, Bao-Jun; Zhang, Zhan-Xue; Li, Ai-Ying; An, Ran; Yue, Bin; Fan, Li-Qiao; Li, Yong

2018-05-01

Objective To investigate the potential antitumour effects of [2-(6-amino-purine-9-yl)-1-hydroxy-phosphine acyl ethyl] phosphonic acid (CP) against gastric adenocarcinoma. Methods Human BGC-823 xenotransplants were established in nude mice. Animals were randomly divided into control and CP groups, which were administered NaHCO 3 vehicle alone or CP dissolved in NaHCO 3 (200 µg/kg body weight) daily, respectively. Tumour volume was measured weekly for 6 weeks. Resected tumours were assayed for proliferative activity with anti-Ki-67 or anti-proliferating cell nuclear antigen (PCNA) antibodies. Cell apoptosis was examined using terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assays and with caspase-3 immunostaining. Proteins were measured by Western blotting. Results There was a significant reduction in tumour volume and a reduced percentage of Ki-67-positive or PCNA-positive cells in the CP group compared with the control group. The percentage of TUNEL-positive or caspase 3-positive cells significantly increased following CP treatment compared with the control group. Tumours from the CP group had higher levels of phosphorylated-extracellular signal-regulated kinase (p-ERK) and phosphorylated-AKT (p-AKT) compared with control tumours. Conclusion CP treatment inhibited tumour growth and induced tumour cell apoptosis in a nude mouse model of BGC-823 gastric adenocarcinoma. Activation of the AKT and ERK signalling pathways may mediate this antitumour activity.

HIFU and Chemotherapy Synergistic Inhibitory Effect on Dunning AT2 Tumour-Bearing Rats

NASA Astrophysics Data System (ADS)

Curiel, Laura; Paparel, Philipe; Chesnais, Sabrina; Gelet, Albert; Chapelon, Jean-Yves

2005-03-01

Since there is no 100% satisfactory treatment for localized prostate cancer in patients presenting symptoms representing a poor prognosis (stage T3, high Gleason score, PSA level greater than 15 ng/ml, etc.), this study aimed to evaluate the therapeutic and synergistic inhibition effects of using High Intensity Focused Ultrasound (HIFU) in combination with chemotherapy (Taxane + Estramustine). Forty-one Dunning AT2 tumour-bearing Copenhagen rats receiving HIFU and/or chemotherapy were divided into four groups: control group; chemotherapy group; HIFU group; and HIFU-chemotherapy combined group. Increase in the tumour volume was observed over 3 weeks and the tumour volume doubling time was evaluated. Growth curves for each group were then plotted and statistically evaluated. HIFU treatment combined with Taxane + Estramusine was found to have a significant synergistic effect; on day 30, the distribution of tumour volume relative to the treatment group was significantly different (p = 0.0007). The control group volumes were significantly greater than those of the chemotherapy-only (p = 0.006) or HIFU-only group (p = 0.006). The greatest difference was observed between the chemotherapy plus HIFU combined group and the control group. Additionally, tumour-doubling times were 7.7 days for the control group, 13.2 days for the HIFU-only group, and 31.2 days for the chemotherapy plus HIFU group. The differences in tumour growth rates between the chemotherapy plus HIFU combined group and a chemotherapy-only + HIFU-only grouping was 3.8% (p = 0.0020). Thus, the combined chemotherapy plus HIFU treatment was clearly more effective in reducing the tumour size than HIFU only or chemotherapy only, which indicates a synergy between the two types of treatment. Our results suggest that this combined therapy could be useful for the treatment of high-risk prostate cancer.

Human herpes simplex viruses in benign and malignant thyroid tumours.

PubMed

Jensen, Kirk; Patel, Aneeta; Larin, Alexander; Hoperia, Victoria; Saji, Motoyasu; Bauer, Andrew; Yim, Kevin; Hemming, Val; Vasko, Vasyl

2010-06-01

To test the hypothesis that herpes viruses may have a role in thyroid neoplasia, we analysed thyroid tissues from patients with benign (44) and malignant (65) lesions for HSV1 and HSV2 DNA. Confirmatory studies included direct sequencing, analysis of viral gene expression, and activation of viral-inducible signalling pathways. Expression of viral entry receptor nectin-1 was examined in human samples and in cancer cell lines. In vitro experiments were performed to explore the molecular mechanisms underlying thyroid cancer cell susceptibility to HSV. HSV DNA was detected in 43/109 (39.4%) examined samples. HSV capsid protein expression correlated with HSV DNA status. HSV-positive tumours were characterized by activation of virus-inducible signalling such as interferon-beta expression and nuclear NFkappaB expression. Lymphocyte infiltration and oncocytic cellular features were common in HSV-positive tumours. HSV1 was detected with the same frequency in benign and malignant thyroid tumours. HSV2 was significantly associated with papillary thyroid cancer and the presence of lymph node metastases. The expression of HSV entry receptor nectin-1 was increased in thyroid tumours compared to normal thyroid tissue and further increased in papillary thyroid cancer. Nectin-1 expression was detected in all examined thyroid cancer cell lines. Nectin-1 expression in cancer cells correlated with their susceptibility to HSV. Inhibition of PI3K/AKT or MAPK/ERK signalling did not affect the level of nectin-1 expression but decreased thyroid cancer cell susceptibility to HSV. These findings showed that HSV is frequently detected in thyroid cancer. During tumour progression, thyroid cells acquire increased susceptibility to HSV due to increased expression of viral entry mediator nectin-1 and activation of mitogenic signalling in cancer cells.

Bilateral multifocal Warthin tumours.

PubMed

Deveer, Mehmet; Sahan, Murat; Sivrioglu, Ali Kemal; Celik, Ozgür Ilhan

2013-05-22

Warthin tumour, also known as papillary cystadenoma lymphomatosum, is the second most frequent benign tumour of the parotid gland after pleomorphic adenoma. A 57-year-old man was referred to our hospital with bilateral buccal masses without pain. He presented with a 1-year history of the condition and stated that growth of the mass has accelerated during the last 6 months. Ultrasonography examination showed two heterogeneous solid masses. Axial contrast-enhanced CT image revealed bilateral heterogeneous solid masses. The masses showed enhancement after contrast administration (95 HU). Fine needle aspiration cytology was recommended for further analysis and typical benign features of Warthin tumour was obtained. Right parotid gland including the masses was resected completely. 5 weeks later superficial parotidectomy was performed to the left parotid gland. Histological examination revealed cystic tumour in the parenchyma of parotid gland, composed of prominent lymphoid stroma and large epithelial cells with oncocytic features covering it consistent with Warthin tumour.

Bilateral multifocal Warthin tumours

PubMed Central

Deveer, Mehmet; Sahan, Murat; Sivrioglu, Ali Kemal; İlhan Celik, Özgür

2013-01-01

Warthin tumour, also known as papillary cystadenoma lymphomatosum, is the second most frequent benign tumour of the parotid gland after pleomorphic adenoma. A 57-year-old man was referred to our hospital with bilateral buccal masses without pain. He presented with a 1-year history of the condition and stated that growth of the mass has accelerated during the last 6 months. Ultrasonography examination showed two heterogeneous solid masses. Axial contrast-enhanced CT image revealed bilateral heterogeneous solid masses. The masses showed enhancement after contrast administration (95 HU). Fine needle aspiration cytology was recommended for further analysis and typical benign features of Warthin tumour was obtained. Right parotid gland including the masses was resected completely. 5 weeks later superficial parotidectomy was performed to the left parotid gland. Histological examination revealed cystic tumour in the parenchyma of parotid gland, composed of prominent lymphoid stroma and large epithelial cells with oncocytic features covering it consistent with Warthin tumour. PMID:23704438

Potential role of TRIM3 as a novel tumour suppressor in colorectal cancer (CRC) development.

PubMed

Piao, Mei-Yu; Cao, Hai-Long; He, Na-Na; Xu, Meng-Que; Dong, Wen-Xiao; Wang, Wei-Qiang; Wang, Bang-Mao; Zhou, Bing

2016-01-01

Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in the United States. Recent cancer genome-sequencing efforts and complementary functional studies have led to the identification of a collection of candidate 'driver' genes involved in CRC tumorigenesis. Tripartite motif (TRIM3) is recently identified as a tumour suppressor in glioblastoma but this tumour-suppressive function has not been investigated in CRC. In this study, we investigated the potential role of TRIM3 as a tumour suppressor in CRC development by manipulating the expression of TRIM3 in two authentic CRC cell lines, HCT116 and DLD1, followed by various functional assays, including cell proliferation, colony formation, scratch wound healing, soft agar, and invasion assays. Xenograft experiment was performed to examine in vivo tumour-suppressive properties of TRIM3. Small-interfering RNA (siRNA) mediated knockdown of TRIM3 conferred growth advantage in CRC cells. In contrast, overexpression of TRIM3 affected cell survival, cell migration, anchorage independent growth and invasive potential in CRC cells. In addition, TRIM3 was found to be down-regulated in human colon cancer tissues compared with matched normal colon tissues. Overexpression of TRIM3 significantly inhibited tumour growth in vivo using xenograft mouse models. Mechanistic investigation revealed that TRIM3 can regulate p53 protein level through its stabilisation. TRIM3 functions as a tumour suppressor in CRC progression. This tumour-suppressive function is exerted partially through regulation of p53 protein. Therefore, this protein may represent a novel therapeutic target for prevention or intervention of CRC.

Suppression of tumour growth by orally administered osteopontin is accompanied by alterations in tumour blood vessels.

PubMed

Rittling, S R; Wejse, P L; Yagiz, K; Warot, G A; Hui, T

2014-03-04

The integrin-binding protein osteopontin is strongly associated with tumour development, yet is an abundant dietary component as a constituent of human and bovine milk. Therefore, we tested the effect of orally administered osteopontin (o-OPN) on the development of subcutaneous tumours in mice. Bovine milk osteopontin was administered in drinking water to tumour-bearing immune-competent mice. Tumour growth, proliferation, necrosis, apoptosis and blood vessel size and number were measured. Expression of the α₉ integrin was determined. o-OPN suppressed tumour growth, increased the extent of necrosis, and induced formation of abnormally large blood vessels. Anti-OPN reactivity detected in the plasma of OPN-null mice fed OPN suggested that tumour-blocking peptides were absorbed during digestion, but the o-OPN effect was likely distinct from that of an RGD peptide. Expression of the α₉ integrin was detected on both tumour cells and blood vessels. Potential active peptides from the α₉ binding site of OPN were identified by mass spectrometry following in vitro digestion, and injection of these peptides suppressed tumour growth. These results suggest that peptides derived from o-OPN are absorbed and interfere with tumour growth and normal vessel development. o-OPN-derived peptides that target the α₉ integrin are likely involved.

CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours

PubMed Central

Costa-Cabral, Sara; Brough, Rachel; Konde, Asha; Aarts, Marieke; Campbell, James; Marinari, Eliana; Riffell, Jenna; Bardelli, Alberto; Torrance, Christopher; Lord, Christopher J.; Ashworth, Alan

2016-01-01

Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent kinase, CDK1. This was discovered using parallel siRNA screens in KRAS mutant and wild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and pancreatic tumour cell models. This established that the KRAS/CDK1 synthetic lethality applies in tumour cells with either amino acid position 12 (p.G12V, pG12D, p.G12S) or amino acid position 13 (p.G13D) KRAS mutations and can also be replicated in vivo in a xenograft model using a small molecule CDK1 inhibitor. Mechanistically, CDK1 inhibition caused a reduction in the S-phase fraction of KRAS mutant cells, an effect also characterised by modulation of Rb, a master control of the G1/S checkpoint. Taken together, these observations suggest that the KRAS/CDK1 interaction is a robust synthetic lethal effect worthy of further investigation. PMID:26881434

Ciliated muconodular papillary tumour of the lung: a newly defined low-grade malignant tumour.

PubMed

Sato, Shuichi; Koike, Teruaki; Homma, Keiichi; Yokoyama, Akira

2010-11-01

We present two cases of ciliated muconodular papillary tumour (CMPT) in this report. CMPT is a newly defined low-grade malignant tumour with ciliated columnar epithelial cells, occurring in the peripheral lung. Both patients underwent pulmonary resection due to an enlarged solitary pulmonary nodule. Pathological findings in both cases confirmed a papillary tumour with a mixture of ciliated columnar and goblet cells. The tumours were rich in mucous and had spread along the alveolar walls, as observed in bronchioloalveolar carcinoma. Nuclear atypia was mild, and no mitotic activity was observed. Immunohistochemically, tumour cells stained positive for carcinoembryonic antigen, thyroid transcription factor-1 and cytokeratin 7 but not for cytokeratin 20. The immunohistochemical staining patterns were almost identical to those of pulmonary adenocarcinoma. We definitively diagnosed as CMPT. Both patients remained relapse-free.

Theranostic barcoded nanoparticles for personalized cancer medicine

PubMed Central

Yaari, Zvi; da Silva, Dana; Zinger, Assaf; Goldman, Evgeniya; Kajal, Ashima; Tshuva, Rafi; Barak, Efrat; Dahan, Nitsan; Hershkovitz, Dov; Goldfeder, Mor; Roitman, Janna Shainsky; Schroeder, Avi

2016-01-01

Personalized medicine promises to revolutionize cancer therapy by matching the most effective treatment to the individual patient. Using a nanoparticle-based system, we predict the therapeutic potency of anticancer medicines in a personalized manner. We carry out the diagnostic stage through a multidrug screen performed inside the tumour, extracting drug activity information with single cell sensitivity. By using 100 nm liposomes, loaded with various cancer drugs and corresponding synthetic DNA barcodes, we find a correlation between the cell viability and the drug it was exposed to, according to the matching barcodes. Based on this screen, we devise a treatment protocol for mice bearing triple-negative breast-cancer tumours, and its results confirm the diagnostic prediction. We show that the use of nanotechnology in cancer care is effective for generating personalized treatment protocols. PMID:27830705

Nanoparticle inhalation alters systemic arteriolar vasoreactivity through sympathetic and cyclooxygenase-mediated pathways

PubMed Central

Knuckles, Travis L.; Yi, Jinghai; Frazer, David G.; Leonard, Howard D.; Chen, Bean T.; Castranova, Vince; Nurkiewicz, Timothy R.

2016-01-01

The widespread increase in the production and use of nanomaterials has increased the potential for nanoparticle exposure; however, the biological effects of nanoparticle inhalation are poorly understood. Rats were exposed to nanosized titanium dioxide aerosols (10 µg lung burden); at 24 h post-exposure, the spinotrapezius muscle was prepared for intravital microscopy. Nanoparticle exposure did not alter perivascular nerve stimulation (PVNS)-induced arteriolar constriction under normal conditions; however, adrenergic receptor inhibition revealed a more robust effect. Nanoparticle inhalation reduced arteriolar dilation in response to active hyperaemia (AH). In both PVNS and AH experiments, nitric oxide synthase (NOS) inhibition affected only controls. Whereas cyclooxygenase (COX) inhibition only attenuated AH-induced arteriolar dilation in nanoparticle-exposed animals. This group displayed an enhanced U46619 constriction and attenuated iloprost-induced dilation. Collectively, these studies indicate that nanoparticle exposure reduces microvascular NO bioavailability and alters COX-mediated vasoreactivity. Furthermore, the enhanced adrenergic receptor sensitivity suggests an augmented sympathetic responsiveness. PMID:21830860

Growth Inhibition of Tumour Implants by Associated Surface Active Agents

PubMed Central

Altman, R. F. A.; Spoladore, L. G.; Esch, E. L.

1970-01-01

Whereas dilute solutions of surface active agents modify the properties of cell membranes, particularly in relation to their electrical behaviour, moderate and strong solutions provoke more serious structural damage of the membrane, leading to an increase of its permeability and, finally, to cytolysis. These phenomena have inspired some authors to apply detergents as possible cancer chemotherapeuticals so far, however, with only poor results. The disintegrating effect of tumour emboli into single cells by certain detergents, and the ingenious discovery that the mutual adhesiveness between cancer cells is much less than between normal cells, have led the present authors to investigate the action of some biological surface active agents, alone as well as in some of their associations on the “take” of Yoshida sarcoma implants. Certain associations showed, in contradistinction to the separately applied components, surprisingly favourable activity. It could be established that a correlation actually exists between inhibitory effect and surface activity. PMID:4394469

Elimination of epithelial-like and mesenchymal-like breast cancer stem cells to inhibit metastasis following nanoparticle-mediated photothermal therapy.

PubMed

Paholak, Hayley J; Stevers, Nicholas O; Chen, Hongwei; Burnett, Joseph P; He, Miao; Korkaya, Hasan; McDermott, Sean P; Deol, Yadwinder; Clouthier, Shawn G; Luther, Tahra; Li, Qiao; Wicha, Max S; Sun, Duxin

2016-10-01

Increasing evidence suggesting breast cancer stem cells (BCSCs) drive metastasis and evade traditional therapies underscores a critical need to exploit the untapped potential of nanotechnology to develop innovative therapies that will significantly improve patient survival. Photothermal therapy (PTT) to induce localized hyperthermia is one of few nanoparticle-based treatments to enter clinical trials in human cancer patients, and has recently gained attention for its ability to induce a systemic immune response targeting distal cancer cells in mouse models. Here, we first conduct classic cancer stem cell (CSC) assays, both in vitro and in immune-compromised mice, to demonstrate that PTT mediated by highly crystallized iron oxide nanoparticles effectively eliminates BCSCs in translational models of triple negative breast cancer. PTT in vitro preferentially targets epithelial-like ALDH + BCSCs, followed by mesenchymal-like CD44+/CD24- BCSCs, compared to bulk cancer cells. PTT inhibits BCSC self-renewal through reduction of mammosphere formation in primary and secondary generations. Secondary implantation in NOD/SCID mice reveals the ability of PTT to impede BCSC-driven tumor formation. Next, we explore the translational potential of PTT using metastatic and immune-competent mouse models. PTT to inhibit BCSCs significantly reduces metastasis to the lung and lymph nodes. In immune-competent BALB/c mice, PTT effectively eliminates ALDH + BCSCs. These results suggest the feasibility of incorporating PTT into standard clinical treatments such as surgery to enhance BCSC destruction and inhibit metastasis, and the potential of such combination therapy to improve long-term survival in patients with metastatic breast cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Feasibility study of Fe₃O₄/TaO_x nanoparticles as a radiosensitizer for proton therapy.

PubMed

Ahn, Sang Hee; Lee, Nohyun; Choi, Changhoon; Shin, Sung Won; Han, Youngyih; Park, Hee Chul

2018-05-04

We investigated the feasibility of using multifunctional Fe3O4/TaOx (core/shell) nanoparticles, developed for use in contrast agents for computed tomography (CT) and magnetic resonance imaging (MRI), as dose-enhancing radiosensitizers. First, to verify the detectability of Fe3O4/TaOx nanoparticles in imaging, in vivo tests were conducted. Approximately 600 mg/kg of 19-nm-diameter Fe3O4/TaOx nanoparticles dispersed in phosphate-buffered saline was injected into the tail vein of six Balb/c mice used as tumour (4T1 mammary carcinoma cell) models. Three mice underwent MRI (BioSpec 70/20 USR, Bruker, Billerica, MA, USA) and micro-CT (Inveon, Siemens Preclinical, Knoxville, TN, USA) before and after the injection. The difference between the pre- and post-injection images was quantified by finding the correlation coefficient. The aorta, blood vessel, and liver were clearly seen in the MRI and micro-CT images 60 min after intravenous injection of Fe3O4/TaOx nanoparticles, but the tumour region was not visible in the CT images until after 24 h. There were large differences between the pre- and post-injection images. Second, the therapeutic enhancement dose of nanomaterials was computed via Monte Carlo simulation. Monoenergetic 70- and 150-MeV proton beams irradiated X-ray contrast agent (iodine, BaSO4) , MRI contrast agent (gadolinium, Fe3O4), Au, Fe3O4/TaOx (core/shell) nanoparticles and water located at the centre of a 4  4  4-μm3 water phantom, upon which the dose enhancement ratio (DER) (dose with/without nanoparticles) was computed. When 70-MeV protons irradiated the Au, gadolinium, Fe3O4/TaOx, Fe3O4, iodine, and BaSO4 nanoparticles, the DERs at 1 nm were 15.76, 7.68, 7.82, 6.17, 4.85, and 5.51, respectively. Fe3O4/TaOx nanoparticles have the potential to be used a multifunctional agent that enhances tumour detection and increases the dose. Dose enhancement with Fe3O4/TaOx was half that with Au. However, Fe3O4/TaOx is much cheaper than Au, and it is expected

Targeting the 19S proteasomal subunit, Rpt4, for the treatment of colon cancer.

PubMed

Boland, Karen; Flanagan, Lorna; McCawley, Niamh; Pabari, Ritesh; Kay, Elaine W; McNamara, Deborah A; Murray, Frank; Byrne, Annette T; Ramtoola, Zebunnissa; Concannon, Caoimhín G; Prehn, Jochen H M

2016-06-05

Deregulation of the ubiquitin-proteasome pathway has been frequently observed in a number of malignancies. Using quantitative Western blotting of normal and matched tumour tissue, we here identified a significant increase in the 19S proteasome subunit Rpt4 in response to chemoradiation in locally advanced rectal cancer patients with unfavourable outcome. We therefore explored the potential of Rpt4 reduction as a therapeutic strategy in colorectal cancer (CRC). Utilizing siRNA to down regulate Rpt4 expression, we show that silencing of Rpt4 reduced proteasomal activity and induced endoplasmic reticulum stress. Gene silencing of Rpt4 also inhibited cell proliferation, reduced clonogenic survival and induced apoptosis in HCT-116 colon cancer cells. We next developed a cell penetrating peptide-based nanoparticle delivery system to achieve in vivo gene silencing of Rpt4. Administration of Rpt4 siRNA nanoparticles reduced tumour growth and improved survival in a HCT-116 colon cancer xenograft tumour model in vivo. Collectively, our data suggest that inhibition of Rpt4 represents a novel strategy for the treatment of CRC. Copyright © 2016 Elsevier B.V. All rights reserved.

Sepsis-induced expansion of granulocytic myeloid-derived suppressor cells promotes tumour growth through Toll-like receptor 4.

PubMed

Llitjos, Jean-François; Auffray, Cédric; Alby-Laurent, Fanny; Rousseau, Christophe; Merdji, Hamid; Bonilla, Nelly; Toubiana, Julie; Belaïdouni, Nadia; Mira, Jean-Paul; Lucas, Bruno; Chiche, Jean-Daniel; Pène, Frédéric

2016-08-01

Severe sepsis remains a frequent and dreaded complication in cancer patients. Beyond the often fatal short-term outcome, the long-term sequelae of severe sepsis may also impact directly on the prognosis of the underlying malignancy in survivors. The immune system is involved in all stages of tumour development, in the detection of transforming and dying cells and in the prevention of tumour growth and dissemination. In fact, the profound and sustained immune defects induced by sepsis may constitute a privileged environment likely to favour tumour growth. We investigated the impact of sepsis on malignant tumour growth in a double-hit animal model of polymicrobial peritonitis, followed by subcutaneous inoculation of MCA205 fibrosarcoma cells. As compared to their sham-operated counterparts, post-septic mice exhibited accelerated tumour growth. This was associated with intratumoural accumulation of CD11b(+) Ly6G(high) polymorphonuclear cells (PMNs) that could be characterized as granulocytic myeloid-derived suppressor cells (G-MDSCs). Depletion of granulocytic cells in post-septic mice inhibited the sepsis-enhanced tumour growth. Toll-like receptor (TLR)-4 (Tlr4) and Myd88 deficiencies prevented sepsis-induced expansion of G-MDSCs and tumour growth. Our results demonstrate that the myelosuppressive environment induced by severe bacterial infections promotes malignant tumour growth, and highlight a critical role of CD11b(+) Ly6G(high) G-MDSCs under the control of TLR-dependent signalling. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Tumours of the upper alimentary tract

PubMed Central

Head, K. W.

1976-01-01

Tumours of the oropharynx of domestic animals are common in most parts of the world, but squamous cell carcinoma of the upper alimentary tract shows differences in prevalence in different geographical areas and occurs at different sites in the various species. Oral tumours of the melanogenic system are more common in dogs than in man. The following main histological categories, which broadly correspond to those used in the classification of tumours of man, are described: papilloma; squamous cell carcinoma; salivary gland tumours; malignant melanoma; tumours of soft (mesenchymal) tissues; tumours of the facial bones; tumours of haematopoietic and related tissues; and odontogenic tumours and jaw cysts. Papilloma, squamous cell carcinoma, malignant melanoma, fibroma, and fibrosarcoma account for about 80% of the tumours that occur in the upper alimentary tract of domestic animals. ImagesFig. 6Fig. 7Fig. 8Fig. 9Fig. 34Fig. 35Fig. 36Fig. 37Fig. 2Fig. 3Fig. 4Fig. 5Fig. 22Fig. 23Fig. 24Fig. 25Fig. 26Fig. 27Fig. 28Fig. 29Fig. 14Fig. 15Fig. 16Fig. 17Fig. 30Fig. 31Fig. 32Fig. 33Fig. 18Fig. 19Fig. 20Fig. 21Fig. 10Fig. 11Fig. 12Fig. 13Fig. 1 PMID:1086147

Nanoparticle strategies for cancer therapeutics: Nucleic acids, polyamines, bovine serum amine oxidase and iron oxide nanoparticles (Review).

PubMed

Agostinelli, Enzo; Vianello, Fabio; Magliulo, Giuseppe; Thomas, Thresia; Thomas, T J

2015-01-01

Nanotechnology for cancer gene therapy is an emerging field. Nucleic acids, polyamine analogues and cytotoxic products of polyamine oxidation, generated in situ by an enzyme-catalyzed reaction, can be developed for nanotechnology-based cancer therapeutics with reduced systemic toxicity and improved therapeutic efficacy. Nucleic acid-based gene therapy approaches depend on the compaction of DNA/RNA to nanoparticles and polyamine analogues are excellent agents for the condensation of nucleic acids to nanoparticles. Polyamines and amine oxidases are found in higher levels in tumours compared to that of normal tissues. Therefore, the metabolism of polyamines spermidine and spermine, and their diamine precursor, putrescine, can be targets for antineoplastic therapy since these naturally occurring alkylamines are essential for normal mammalian cell growth. Intracellular polyamine concentrations are maintained at a cell type-specific set point through the coordinated and highly regulated interplay between biosynthesis, transport, and catabolism. In particular, polyamine catabolism involves copper-containing amine oxidases. Several studies showed an important role of these enzymes in developmental and disease-related processes in animals through the control of polyamine homeostasis in response to normal cellular signals, drug treatment, and environmental and/or cellular stress. The production of toxic aldehydes and reactive oxygen species (ROS), H2O2 in particular, by these oxidases suggests a mechanism by which amine oxidases can be exploited as antineoplastic drug targets. The combination of bovine serum amine oxidase (BSAO) and polyamines prevents tumour growth, particularly well if the enzyme has been conjugated with a biocompatible hydrogel polymer. The findings described herein suggest that enzymatically formed cytotoxic agents activate stress signal transduction pathways, leading to apoptotic cell death. Consequently, superparamagnetic nanoparticles or other

Periadventitial Application of Rapamycin-Loaded Nanoparticles Produces Sustained Inhibition of Vascular Restenosis

PubMed Central

Guo, Lian-Wang; Si, Yi; Zhu, Men; Pilla, Srikanth; Liu, Bo; Gong, Shaoqin; Kent, K. Craig

2014-01-01

Open vascular reconstructions frequently fail due to the development of recurrent disease or intimal hyperplasia (IH). This paper reports a novel drug delivery method using a rapamycin-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs)/pluronic gel system that can be applied periadventitially around the carotid artery immediately following the open surgery. In vitro studies revealed that rapamycin dispersed in pluronic gel was rapidly released over 3 days whereas release of rapamycin from rapamycin-loaded PLGA NPs embedded in pluronic gel was more gradual over 4 weeks. In cultured rat vascular smooth muscle cells (SMCs), rapamycin-loaded NPs produced durable (14 days versus 3 days for free rapamycin) inhibition of phosphorylation of S6 kinase (S6K1), a downstream target in the mTOR pathway. In a rat balloon injury model, periadventitial delivery of rapamycin-loaded NPs produced inhibition of phospho-S6K1 14 days after balloon injury. Immunostaining revealed that rapamycin-loaded NPs reduced SMC proliferation at both 14 and 28 days whereas rapamycin alone suppressed proliferation at day 14 only. Moreover, rapamycin-loaded NPs sustainably suppressed IH for at least 28 days following treatment, whereas rapamycin alone produced suppression on day 14 with rebound of IH by day 28. Since rapamycin, PLGA, and pluronic gel have all been approved by the FDA for other human therapies, this drug delivery method could potentially be translated into human use quickly to prevent failure of open vascular reconstructions. PMID:24586612

Overcoming resistance to molecularly targeted anticancer therapies: Rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies.

PubMed

Tortora, Giampaolo; Bianco, Roberto; Daniele, Gennaro; Ciardiello, Fortunato; McCubrey, James A; Ricciardi, Maria Rosaria; Ciuffreda, Ludovica; Cognetti, Francesco; Tafuri, Agostino; Milella, Michele

2007-06-01

Accumulating evidence suggests that cancer can be envisioned as a "signaling disease", in which alterations in the cellular genome affect the expression and/or function of oncogenes and tumour suppressor genes. This ultimately disrupts the physiologic transmission of biochemical signals that normally regulate cell growth, differentiation and programmed cell death (apoptosis). From a clinical standpoint, signal transduction inhibition as a therapeutic strategy for human malignancies has recently achieved remarkable success. However, as additional drugs move forward into the clinical arena, intrinsic and acquired resistance to "targeted" agents becomes an issue for their clinical utility. One way to overcome resistance to targeted agents is to identify genetic and epigenetic aberrations underlying sensitivity/resistance, thus enabling the selection of patients that will most likely benefit from a specific therapy. Since resistance often ensues as a result of the concomitant activation of multiple, often overlapping, signaling pathways, another possibility is to interfere with multiple, cross-talking pathways involved in growth and survival control in a rational, mechanism-based, fashion. These concepts may be usefully applied, among others, to agents that target two major signal transduction pathways: the one initiated by epidermal growth factor receptor (EGFR) signaling and the one converging on mitogen-activated protein kinase (MAPK) activation. Here, we review the molecular mechanisms of sensitivity/resistance to EGFR inhibitors, as well as the rationale for combining them with other targeted agents, in an attempt to overcome resistance. In the second part of the paper, we review MAPK-targeted agents, focusing on their therapeutic potential in haematologic malignancies, and examine the prospects for combinations of MAPK inhibitors with cytotoxic agents or other signal transduction-targeted agents to obtain synergistic anti-tumour effects.

Mitomycin C in combination with radiotherapy as a potent inhibitor of tumour cell repopulation in a human squamous cell carcinoma

PubMed Central

Budach, W; Paulsen, F; Welz, S; Classen, J; Scheithauer, H; Marini, P; Belka, C; Bamberg, M

2002-01-01

The potential of Mitomycin C in combination with fractionated irradiation to inhibit tumour cell repopulation of a fast growing squamous cell carcinoma after fractionated radiotherapy was investigated in vivo. A rapidly growing human squamous cell carcinoma (FaDudd) was used for the study. For experiments, NMRI (nu/nu) mice with subcutaneously growing tumours were randomly allocated to no treatment, Mitomycin C, fractionated irradiation (ambient: 11x4.5 Gy in 15 days), or fractionated irradiation combined with Mitomycin C. Graded top up doses (clamped blood flow: 0–57 Gy) were given at day 16, 23, 30 or 37. End point of the study was the time to local tumour progression. Data were examined by multiple regression analysis (Cox). Mitomycin C alone resulted in a median time to local tumour progression of 23 (95% confidence limits: 17–43) days, fractionated irradiation in 31 (25–35) days and combined Mitomycin C plus fractionated irradiation in 65 (58–73) days (P=0.02). Mitomycin C decreased the relative risk of local recurrence by 94% (P<<0.001) equivalent to 31.7 Gy top up dose. Repopulation accounted for 1.33 (0.95–1.72) Gy per day top up dose after fractionated irradiation alone and for 0.68 (0.13–1.22) Gy per day after fractionated irradiation+Mitomycin C (P=0.018). Mitomycin C significantly reduces the risk of local recurrence and inhibits tumour cell repopulation in combination with fractionated irradiation in vivo in the tested tumour model. British Journal of Cancer (2002) 86, 470–476. DOI: 10.1038/sj/bjc/6600081 www.bjcancer.com © 2002 The Cancer Research Campaign PMID:11875717

CD34 + tumours of the orbit including solitary fibrous tumours: a six-case series.

PubMed

Jung, Su Kyung; Paik, Ji Sun; Park, Gyeong Sin; Yang, Suk-Woo

2017-04-27

To report six cases of CD34+ fibroblastic mesenchymal tumours, which are uncommon neoplasms in the orbit. Six patients presenting with proptosis and palpable mass who were later diagnosed with fibrous solitary tumours, fibrous histocytoma or haemangiopericytoma in the orbit were included. All patients received radiologic examinations and surgical excision for histopathology and immunohistochemistry examinations. Five patients had no recurrence after a minimum follow-up of 12 months. One patient (case 6) experienced recurrence twice, and had debulking surgeries each time. At present, the patient still has remnant tumour in the orbit, but no growth has been detected during the past two years. The tumour size will be closely monitored. Even though fibroblastic tumours are rarely found in the orbit, they can present as a palpable mass with proptosis. Complete surgical excision is important for long-term prognosis, and immunohistochemical study is helpful for confirming pathologic diagnosis.

Gallic acid-capped gold nanoparticles inhibit EGF-induced MMP-9 expression through suppression of p300 stabilization and NFκB/c-Jun activation in breast cancer MDA-MB-231 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Ying-Jung; Lee, Yuan-Chin; Huang, Chia-Hui

Triple-negative breast cancers (TNBCs) are highly invasive and have a higher rate of distant metastasis. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in EGF/EGFR-mediated malignant progression and metastasis of TNBCs. Various studies have revealed that treatment with gallic acid down-regulates MMP-9 expression in cancer cells, and that conjugation of phytochemical compounds with gold nanoparticles (AuNPs) increases the anti-tumor activity of the phytochemical compounds. Thus, the effect of gallic acid-capped AuNPs (GA-AuNPs) on MMP-9 expression in EGF-treated TNBC MDA-MB-231 cells was analyzed in the present study. The so-called green synthesis of AuNPs by means of gallic acid was performed at pHmore » 10, and the resulting GA-AuNPs had spherical shape with an average diameter of approximately 50 nm. GA-AuNPs notably suppressed migration and invasion of EGF-treated cells, and inhibited EGF-induced MMP-9 up-regulation. GA-AuNPs abrogated EGF-induced Akt/p65 and ERK/c-Jun phosphorylation, leading to down-regulation of MMP-9 mRNA and protein expression in EGF-treated cells. Meanwhile, EGF-induced p300 stabilization was found to be involved in MMP-9 expression, whereas GA-AuNPs inhibited the EGF-promoted stability of the p300 protein. Although GA-AuNPs and gallic acid suppressed EGF-induced MMP-9 up-regulation via the same signaling pathway, the effective concentration of gallic acid was approximately 100-fold higher than that of GA-AuNPs for inhibition of MMP-9 expression in EGF-treated cells to a similar extent. Collectively, our data indicate that, in comparison with gallic acid, GA-AuNPs have a superior ability to inhibit EGF/EGFR-mediated MMP-9 expression in TNBC MDA-MB-231 cells. Our findings also point to a way to improve the anti-tumor activity of gallic acid. - Highlights: • Gallic acid-capped gold nanoparticles inhibit EGF-induced MMP-9 expression. • EGF-induced MMP-9 expression via p300 stabilization and NFκB/c-Jun activation. • Gallic

Tumours of the soft (mesenchymal) tissues.

PubMed

Weiss, E

1974-01-01

This is a classification of tumours of fibrous tissue, fat, muscle, blood and lymph vessels, and mast cells, irrespective of the region of the body in which they arise. Tumours of fibrous tissue are divided into fibroma, fibrosarcoma (including "canine haemangiopericytoma"), other sarcomas, equine sarcoid, and various tumour-like lesions. The histological appearance of the tumours is described and illustrated with photographs.

The substances of plant origin that inhibit protein biosynthesis.

PubMed

Gałasiński, W; Chlabicz, J; Paszkiewicz-Gadek, A; Marcinkiewicz, C; Gindzieński, A

1996-01-01

Some plants were used for a long time in folk medicine as sources of anti-tumour remedies. Their effects on protein biosynthesis in vitro have been examined and described. The separate features of the peptide elongation system, isolated from tumoural cells, have been demonstrated. Some elongation factors or ribosomes have been shown to be a target site for the inhibition of protein biosynthesis caused by the substances isolated from various sources. The glycoside and caffeic acid, isolated from Melissa officinalis leaves, inhibited protein biosynthesis by direct influence the elongation factor eEF-2. The activity of this factor was also inhibited by aloin and aloeemodin. Saponin glycoside and its aglycon, isolated from Verbascum thapsiforme flowers, as well as digoxin, emetine and cepheline directly inactivated ribosomes. "Chagi" fraction, isolated from Inonotus obliquus, is responsible for the inhibitory effect caused by the aqueous tannin--less extract from this fungus. The target site for quercetin has been found to be the subunit form EF-1 alpha. It may be supposed that, the plant inhibitors of protein biosynthesis could be utilized for searching specific antitumoural preparations.

Selective activation of p53-mediated tumour suppression in high-grade tumours.

PubMed

Junttila, Melissa R; Karnezis, Anthony N; Garcia, Daniel; Madriles, Francesc; Kortlever, Roderik M; Rostker, Fanya; Brown Swigart, Lamorna; Pham, David M; Seo, Youngho; Evan, Gerard I; Martins, Carla P

2010-11-25

Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10-15%. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras. p53 is also frequently inactivated in NSCLC and, because oncogenic Ras can be a potent trigger of p53 (ref. 3), it seems likely that oncogenic Ras signalling has a major and persistent role in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease. Here we model the probable therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras. Surprisingly, p53 restoration failed to induce significant regression of established tumours, although it did result in a significant decrease in the relative proportion of high-grade tumours. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signalling sensor p19(ARF)( )(ref. 6). Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers.

Grafting of 4-aminomethylbenzensulfonamide-lipoic acid conjugate on gold nanoparticles

NASA Astrophysics Data System (ADS)

Stiti, M.; Bouzit, H.; Abdaoui, M.; Winum, J. Y.

2012-02-01

In this paper, we describe the synthesis of goldnanoparticles bearing aminomethylbenzensulfonamide via a lipoyl moiety. The resulting stable nanoparticles with an average size of 4.0 nm have been achieved by a facile and high-yielding one phase method, by the action of 4-aminomethylbenzensulfonamide-lipoic acid bioconjugate on chloroauric acide, using dimethylsulfoxide (DMSO) as the solvent and sodium tetrahydridoborate (NaBH4) as the reducing agent. UV-vis absorption, transmission electron microscopy (TEM) and X-ray diffraction were used to analyse the morphology and the structure of the obtained nanoparticles. Preliminary study shows that these new nanoparticles are endowed with highly and specific inhibitory activity for the isoform (IX) of carbonic anhydrase over expressed in many cancers, and are therefore attractive candidate to be used both in diagnosis and in treatment of tumours.

Peculiarities of hyperlipidaemia in tumour patients.

PubMed Central

Dilman, V. M.; Berstein, L. M.; Ostroumova, M. N.; Tsyrlina, Y. V.; Golubev, A. G.

1981-01-01

The study group included 684 cases: 258 patients with breast carcinoma, 113 males with lung cancer, 42 patients with rectal tumours, 42 patients with stomach tumours, 59 patients with fibroadenomatosis, and 170 healthy subjects of varying age (male and female). A relatively high blood triglyceride level was found in patients with breast, lung, rectal (females), and stomach (female) tumours. The blood concentration of high-density lipoprotein-cholesterol in patients with breast, lung, and stomach (female) tumours was relatively low. The elimination of tumour (breast carcinoma) did not lead to significant changes in lipid metabolism. There was no correlation between degree of lipidaemia and stage of tumour progression except in the cases of rectal cancer. Preliminary results are presented on the tentative classification of hyperlipoproteinaemia in tumour patients, using the lipid concentration threshold values advocated by Carlson et al. (1977); an increased frequency of Type IV hyperlipoproteinaemia proved to be the most characteristic feature of tumour patients. The results are discussed in terms of the concept of the importance of lipid metabolic disturbances, primarily those due to ageing, in the genesis of the syndrome of "cancerophilia" (predisposition to cancer). PMID:7248149

Peculiarities of hyperlipidaemia in tumour patients.

PubMed

Dilman, V M; Berstein, L M; Ostroumova, M N; Tsyrlina, Y V; Golubev, A G

1981-05-01

The study group included 684 cases: 258 patients with breast carcinoma, 113 males with lung cancer, 42 patients with rectal tumours, 42 patients with stomach tumours, 59 patients with fibroadenomatosis, and 170 healthy subjects of varying age (male and female). A relatively high blood triglyceride level was found in patients with breast, lung, rectal (females), and stomach (female) tumours. The blood concentration of high-density lipoprotein-cholesterol in patients with breast, lung, and stomach (female) tumours was relatively low. The elimination of tumour (breast carcinoma) did not lead to significant changes in lipid metabolism. There was no correlation between degree of lipidaemia and stage of tumour progression except in the cases of rectal cancer. Preliminary results are presented on the tentative classification of hyperlipoproteinaemia in tumour patients, using the lipid concentration threshold values advocated by Carlson et al. (1977); an increased frequency of Type IV hyperlipoproteinaemia proved to be the most characteristic feature of tumour patients. The results are discussed in terms of the concept of the importance of lipid metabolic disturbances, primarily those due to ageing, in the genesis of the syndrome of "cancerophilia" (predisposition to cancer).

Metastasising pilar tumour of scalp.

PubMed Central

Batman, P A; Evans, H J

1986-01-01

A case of pilar tumour of the scalp, treated by local excision and radiotherapy, later metastasised to the neck. The variable histological growth patterns of the primary tumour and its metastases are described. It is concluded that the pilar tumour is a genuine neoplasm of the hair follicle that is occasionally capable of malignant behaviour. Images PMID:3734112

Growth inhibition of malignant melanoma by intermediate frequency alternating electric fields, and the underlying mechanisms.

PubMed

Chen, H; Liu, R; Liu, J; Tang, J

2012-01-01

This study investigated the antitumour effects of intermediate frequency alternating electric fields (IF-AEF) in a murine melanoma cell line (B16F10) and a mouse tumour model. IF-AEF was applied at 100 kHz. Proliferation of B16F10 cells in vitro was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. IF-AEF was applied in vivo to mice bearing B16F10 tumours. Terminal deoxy nucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay for apoptosis, and immunohistochemical detection of CD34 and vascular endothelial growth factor (VEGF), were performed. IF-AEF inhibited the proliferation of B16F10 cells in an electrical intensity and time-dependent manner. Treatment with IF-AEF for 7 days significantly inhibited the growth of tumours compared with untreated controls. IF-AEF induced apoptosis in vivo and reduced CD34-positive cell numbers; CD34 is a special marker of microvessel density. IF-AEF reduced microvessel density related to tumour growth and may serve as a therapeutic strategy for cancer treatment.

A forgotten facial nerve tumour: granular cell tumour of the parotid and its implications for treatment.

PubMed

Lerut, B; Vosbeck, J; Linder, T E

2011-04-01

We present a rare case of a facial nerve granular cell tumour in the right parotid gland, in a 10-year-old boy. A parotid or neurogenic tumour was suspected, based on magnetic resonance imaging. Intra-operatively, strong adhesions to surrounding structures were found, and a midfacial nerve branch had to be sacrificed for complete tumour removal. Recent reports verify that granular cell tumours arise from Schwann cells of peripheral nerve branches. The rarity of this tumour within the parotid gland, its origin from peripheral nerves, its sometimes misleading imaging characteristics, and its rare presentation with facial weakness and pain all have considerable implications on the surgical strategy and pre-operative counselling. Fine needle aspiration cytology may confirm the neurogenic origin of this lesion. When resecting the tumour, the surgeon must anticipate strong adherence to the facial nerve and be prepared to graft, or sacrifice, certain branches of this nerve.

Gene transfer preferentially selects MHC class I positive tumour cells and enhances tumour immunogenicity.

PubMed

Hacker, Ulrich T; Schildhauer, Ines; Barroso, Margarita Céspedes; Kofler, David M; Gerner, Franz M; Mysliwietz, Josef; Buening, Hildegard; Hallek, Michael; King, Susan B S

2006-05-01

The modulated expression of MHC class I on tumour tissue is well documented. Although the effect of MHC class I expression on the tumorigenicity and immunogenicity of MHC class I negative tumour cell lines has been rigorously studied, less is known about the validity of gene transfer and selection in cell lines with a mixed MHC class I phenotype. To address this issue we identified a C26 cell subline that consists of distinct populations of MHC class I (H-2D/K) positive and negative cells. Transient transfection experiments using liposome-based transfer showed a lower transgene expression in MHC class I negative cells. In addition, MHC class I negative cells were more sensitive to antibiotic selection. This led to the generation of fully MHC class I positive cell lines. In contrast to C26 cells, all transfectants were rejected in vivo and induced protection against the parental tumour cells in rechallenge experiments. Tumour cell specificity of the immune response was demonstrated in in vitro cytokine secretion and cytotoxicity assays. Transfectants expressing CD40 ligand and hygromycin phosphotransferase were not more immunogenic than cells expressing hygromycin resistance alone. We suggest that the MHC class I positive phenotype of the C26 transfectants had a bearing on their immunogenicity, because selected MHC class I positive cells were more immunogenic than parental C26 cells and could induce specific anti-tumour immune responses. These data demonstrate that the generation of tumour cell transfectants can lead to the selection of subpopulations that show an altered phenotype compared to the parental cell line and display altered immunogenicity independent of selection marker genes or other immune modulatory genes. Our results show the importance of monitoring gene transfer in the whole tumour cell population, especially for the evaluation of in vivo therapies targeted to heterogeneous tumour cell populations.

Inhibition of hemangioma growth using polymer-lipid hybrid nanoparticles for delivery of rapamycin.

PubMed

Li, Haitao; Teng, Yunfei; Sun, Jin; Liu, Jianyong

2017-11-01

Although infantile hemangiomas is benign, its rapid growth may induce serious complications. However, only one drug Hemangeol™ has been approved by US Food and Drug Administration (FDA) to treat infantile hemangiomas. Thus it is necessary to develop novel alternative drugs to treat infantile hemangiomas. Rapamycin is a well-know potent antiangiogenic agent, whereas the daily oral administration of rapamycin exerts undesired metabolic effects due to its inhibition of mechanistic target of rapamycin (mTOR) which is critical in cell metabolism. We hereby developed rapamycin-loaded polymer-lipid hybrid nanoparticles (Rapamycin-PLNPs) as a local controlled release system to realize local and sustained release of rapamycin, aiming to reduce the side effects and frequency of administration of rapamycin. Rapamycin-PLNPs are of a small size (129.1nm), desired drug encapsulation efficiency (63.7%), and sustained drug release for 5 days. Rapamycin-PLNPs were shown to be able to effectively bind to hemangioma endothelia cells (HemECs), induce significant proliferation inhibition and reduce expression of angiogenesis factors in HemECs. The therapeutic effect of Rapamycin-PLNPs against infantile hemangioma in vivo was superior to rapamycin, as reflected by reduced hemangioma volume, weight and microvessel density. Taken together, Rapamycin-PLNPs represent a very promising local approach in the treatment of infantile hemangiomas. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Expression of podoplanin in Warthin tumours.

PubMed

Hansen, Torsten; Kirkpatrick, C James

2010-12-01

Warthin tumour is the second most common benign tumour of the parotid gland. This study was designed to investigate the lymphatic vessels in Warthin tumours in an effort to understand better its pathogenesis. Tissue specimens of 31 patients (19 men and 11 women; mean age 57 years, median size of the tumours 2.86 cm) were analysed by means of immunohistochemistry applying the monoclonal antibody D2-40. We found numerous D2-40-positive sinus-like vessels particularly at the inner layer of the capsule. Since subcapsular sinuses are a major morphological feature of lymph nodes in general, the finding of podoplanin expression in the large majority of subcapsular vessels in Warthin tumours confirms the view that this tumour has its origin in regional lymph nodes.

Canine transmissible venereal tumour: a morphological and immunohistochemical study of 11 tumours in growth phase and during regression after chemotherapy.

PubMed

Gonzalez, C M; Griffey, S M; Naydan, D K; Flores, E; Cepeda, R; Cattaneo, G; Madewell, B R

2000-05-01

Eleven dogs with canine transmissible venereal tumour (CTVT) were given vincristine sulphate chemotherapy to induce tumour regression. Biopsy specimens were collected from tumours during the growth phase, before chemotherapy, and again from the same dogs during the regression induced by chemotherapy. Laboratory assessment included cytology, histology, the number of tumour cells in relation to the number of intratumoral leucocytes, proliferative and apoptotic fractions of tumour cells, intratumoral vessel density, and fibrosis. The results revealed that during regression, tumour cell proliferation ceased, apoptosis increased, leucocytes increased (with increased proportion of T lymphocytes), tumour parenchyma collapsed around intratumoral vessels, and fibrosis increased. These results, which were similar to findings in dogs with spontaneous regression of CTVT, suggest that tumour immunity plays a role in tumour regression after modest chemotherapy. Copyright 2000 Harcourt Publishers Ltd.

Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug

PubMed Central

Miller, Miles A.; Zheng, Yao-Rong; Gadde, Suresh; Pfirschke, Christina; Zope, Harshal; Engblom, Camilla; Kohler, Rainer H.; Iwamoto, Yoshiko; Yang, Katherine S.; Askevold, Bjorn; Kolishetti, Nagesh; Pittet, Mikael; Lippard, Stephen J.; Farokhzad, Omid C.; Weissleder, Ralph

2015-01-01

Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behaviour. Model TNPs comprising a fluorescent platinum(IV) pro-drug and a clinically tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumour-associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA-damaging Pt payload gradually releases to neighbouring tumour cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials. PMID:26503691

Ga(III) Nanoparticles Inhibit Growth of both Mycobacterium tuberculosis and HIV and Release of Interleukin-6 (IL-6) and IL-8 in Coinfected Macrophages

PubMed Central

Choi, Seoung-ryoung; Britigan, Bradley E.

2017-01-01

ABSTRACT Treatment of individuals coinfected with human immunodeficiency virus (HIV) type 1 and Mycobacterium tuberculosis is challenging due to the prolonged treatment requirements, drug toxicity, and emergence of drug resistance. Mononuclear phagocytes (MP; macrophages) are one of the natural reservoirs for both HIV and M. tuberculosis. Here, the treatment of HIV and M. tuberculosis coinfection was studied by preloading human macrophages with MP-targeted gallium (Ga) nanoparticles to limit subsequent simultaneous infection with both HIV and M. tuberculosis. Ga nanoparticles provided sustained drug release for 15 days and significantly inhibited the replication of both HIV and M. tuberculosis. Addition of Ga nanoparticles to MP already infected with M. tuberculosis or HIV resulted in a significant decrease in the magnitude of these infections, but the magnitude was less than that achieved with nanoparticle preloading of the MP. In addition, macrophages that were coinfected with HIV and M. tuberculosis and that were loaded with Ga nanoparticles reduced the levels of interleukin-6 (IL-6) and IL-8 secretion for up to 15 days after drug loading. Ga nanoparticles also reduced the levels of IL-6 and IL-8 secretion by ionomycin- and lipopolysaccharide-induced macrophages, likely by modulating the IκB kinase-β/NF-κB pathway. Delivery of Ga nanoparticles to macrophages is a potent long-acting approach for suppressing HIV and M. tuberculosis coinfection of macrophages in vitro and sets the stage for the development of new approaches to the treatment of these important infections. PMID:28167548

Light-triggered methylcellulose gold nanoparticle hydrogels for leptin release to inhibit fat stores in adipocytes.

PubMed

Liao, Zi-Xian; Liu, Meng-Chia; Kempson, Ivan M; Fa, Yu-Chen; Huang, Kuo-Yen

2017-01-01

Leptin is released in response to increased triglyceride storage in adipocytes and impacts body weight, but has drawbacks such as poor therapeutic effect and side effects when delivered systemically. Leptin also modifies adipocyte sensitivity to insulin to inhibit lipid accumulation. Here, light-triggered degradation of hydrogels was used to improve accuracy and effectiveness for sustained and controllable release. In our approach, leptin was entrapped within methylcellulose (MC)-based hydrogels, with incorporation of gold nanoparticles (NP). The incorporation of gold NP into MC hydrogels led to a tunable light irradiation response that dictated the hydrogel release rate of leptin. This manuscript demonstrates feasibility in designing tunable thermosensitive hydrogels for loading multimodality therapeutic agents to enhance the bioactivity of leptin for obesity therapy.

That which does not kill me makes me stronger; combining ERK1/2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance

PubMed Central

Sale, Matthew J; Cook, Simon J

2013-01-01

Oncogenic mutations in RAS or BRAF can drive the inappropriate activation of the ERK1/2. In many cases, tumour cells adapt to become addicted to this deregulated ERK1/2 signalling for their proliferation, providing a therapeutic window for tumour-selective growth inhibition. As a result, inhibition of ERK1/2 signalling by BRAF or MEK1/2 inhibitors is an attractive therapeutic strategy. Indeed, the first BRAF inhibitor, vemurafenib, has now been approved for clinical use, while clinical evaluation of MEK1/2 inhibitors is at an advanced stage. Despite this progress, it is apparent that tumour cells adapt quickly to these new targeted agents so that tumours with acquired resistance can emerge within 6–9 months of primary treatment. One of the major reasons for this is that tumour cells typically respond to BRAF or MEK1/2 inhibitors by undergoing a G1 cell cycle arrest rather than dying. Indeed, although inhibition of ERK1/2 invariably increases the expression of pro-apoptotic BCL2 family proteins, tumour cells undergo minimal apoptosis. This cytostatic response may simply provide the cell with the opportunity to adapt and acquire resistance. Here we discuss recent studies that demonstrate that combination of BRAF or MEK1/2 inhibitors with inhibitors of pro-survival BCL2 proteins is synthetic lethal for ERK1/2-addicted tumour cells. This combination effectively transforms the cytostatic response of BRAF and MEK1/2 inhibitors into a striking apoptotic cell death response. This not only augments the primary efficacy of BRAF and MEK1/2 inhibitors but delays the onset of acquired resistance to these agents, validating their combination in the clinic. Linked Articles This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8 PMID:23647573

A robust screening method for dietary agents that activate tumour-suppressor microRNAs

PubMed Central

Hagiwara, Keitaro; Gailhouste, Luc; Yasukawa, Ken; Kosaka, Nobuyoshi; Ochiya, Takahiro

2015-01-01

Certain dietary agents, such as natural products, have been reported to show anti-cancer effects. However, the underlying mechanisms of these substances in human cancer remain unclear. We recently found that resveratrol exerts an anti-cancer effect by upregulating tumour-suppressor microRNAs (miRNAs). In the current study, we aimed to identify new dietary products that have the ability to activate tumour-suppressor miRNAs and that therefore may serve as novel tools for the prevention and treatment of human cancers. We describe the generation and use of an original screening system based on a luciferase-based reporter vector for monitoring miR-200c tumour-suppressor activity. By screening a library containing 139 natural substances, three natural compounds — enoxolone, magnolol and palmatine chloride — were identified as being capable of inducing miR-200c expression in breast cancer cells at 10 μM. Moreover, these molecules suppressed the invasiveness of breast cancer cells in vitro. Next, we identified a molecular pathway by which the increased expression of miR-200c induced by natural substances led to ZEB1 inhibition and E-cadherin induction. These results indicate that our method is a valuable tool for a fast identification of natural molecules that exhibit tumour-suppressor activity in human cancer through miRNA activation. PMID:26423775

Suspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells

PubMed Central

Liu, Chen-Chi; Lin, Shih-Pei; Hsu, Han-Shui; Yang, Shung-Haur; Lin, Chiu-Hua; Yang, Muh-Hwa; Hung, Mien-Chie; Hung, Shih-Chieh

2016-01-01

Targeting tumour-initiating cells (TICs) would lead to new therapies to cure cancer. We previously demonstrated that TICs have the capacity to survive under suspension conditions, while other cells undergo anoikis. Here we show that TICs exhibit increased phosphorylation levels of S727STAT3 because of PP2A inactivation. Collagen 17 gene expression is upregulated in a STAT3-dependent manner, which also stabilizes laminin 5 and engages cells to form hemidesmosome-like junctions in response. Blocking the PP2A-S727STAT3-collagen 17 pathway inhibits the suspension survival of TICs and their ability to form tumours in mice, while activation of the same pathway increases the suspension survival and tumour-initiation capacities of bulk cancer cells. The S727STAT3 phosphorylation levels correlate with collagen 17 expression in colon tumour samples, and correlate inversely with survival. Finally, this signalling axis enhances the ability of TIC to form tumours in mouse models of malignant lung cancer pleural effusion and spontaneous colon cancer metastasis. PMID:27306323

Suspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells.

PubMed

Liu, Chen-Chi; Lin, Shih-Pei; Hsu, Han-Shui; Yang, Shung-Haur; Lin, Chiu-Hua; Yang, Muh-Hwa; Hung, Mien-Chie; Hung, Shih-Chieh

2016-06-16

Targeting tumour-initiating cells (TICs) would lead to new therapies to cure cancer. We previously demonstrated that TICs have the capacity to survive under suspension conditions, while other cells undergo anoikis. Here we show that TICs exhibit increased phosphorylation levels of S727STAT3 because of PP2A inactivation. Collagen 17 gene expression is upregulated in a STAT3-dependent manner, which also stabilizes laminin 5 and engages cells to form hemidesmosome-like junctions in response. Blocking the PP2A-S727STAT3-collagen 17 pathway inhibits the suspension survival of TICs and their ability to form tumours in mice, while activation of the same pathway increases the suspension survival and tumour-initiation capacities of bulk cancer cells. The S727STAT3 phosphorylation levels correlate with collagen 17 expression in colon tumour samples, and correlate inversely with survival. Finally, this signalling axis enhances the ability of TIC to form tumours in mouse models of malignant lung cancer pleural effusion and spontaneous colon cancer metastasis.

Anomalous antibacterial activity and dye degradation by selenium doped ZnO nanoparticles.

PubMed

Dutta, Raj Kumar; Nenavathu, Bhavani Prasad; Talukdar, Soumita

2014-02-01

Selenium doped ZnO nanoparticles synthesized by mechanochemical method were spherically shaped of size distribution of 10.2±3.4 nm measured by transmission electron microscopy. Diffused reflectance spectroscopy revealed increase in the band gap, ranging between 3.47 eV and 3.63 eV due to Se doping in ZnO nanoparticles. The antibacterial activity of pristine and Se doped ZnO nanoparticles was attributed to ROS (reactive oxygen species) generation in culture media confirmed by TBARS assay. Compared to complete inhibition of growth by 0.45 mg/mL of pristine ZnO nanoparticles, the batches of 0.45 mg/mL of selenium doped ZnO nanoparticles exhibited only 51% inhibition of growth of Escherichia coli. The reduced antibacterial activity of selenium doped ZnO nanoparticles was attributed to two opposing factors, e.g., ROS generation for inhibition of growth, countered by sustaining growth of E. coli due to availability of Se micronutrients in culture media, confirmed by inductively coupled plasma mass spectrometer measurement. Higher ROS generation by selenium doped ZnO nanoparticles was attributed to creation of oxygen vacancies, confirmed from green emission peak observed at 565 nm. The impact of higher ROS generation by selenium doped ZnO nanoparticles was evident from enhanced photocatalytic degradation of trypan blue dye, than pristine ZnO nanoparticles. Copyright © 2013 Elsevier B.V. All rights reserved.

Modelling the Transport of Nanoparticles under Blood Flow using an Agent-based Approach.

PubMed

Fullstone, Gavin; Wood, Jonathan; Holcombe, Mike; Battaglia, Giuseppe

2015-06-10

Blood-mediated nanoparticle delivery is a new and growing field in the development of therapeutics and diagnostics. Nanoparticle properties such as size, shape and surface chemistry can be controlled to improve their performance in biological systems. This enables modulation of immune system interactions, blood clearance profile and interaction with target cells, thereby aiding effective delivery of cargo within cells or tissues. Their ability to target and enter tissues from the blood is highly dependent on their behaviour under blood flow. Here we have produced an agent-based model of nanoparticle behaviour under blood flow in capillaries. We demonstrate that red blood cells are highly important for effective nanoparticle distribution within capillaries. Furthermore, we use this model to demonstrate how nanoparticle size can selectively target tumour tissue over normal tissue. We demonstrate that the polydispersity of nanoparticle populations is an important consideration in achieving optimal specificity and to avoid off-target effects. In future this model could be used for informing new nanoparticle design and to predict general and specific uptake properties under blood flow.

PE38KDEL-loaded anti-HER2 nanoparticles inhibit breast tumor progression with reduced toxicity and immunogenicity.

PubMed

Gao, Jie; Kou, Geng; Wang, Hao; Chen, Huaiwen; Li, Bohua; Lu, Ying; Zhang, Dapeng; Wang, Shuhui; Hou, Sheng; Qian, Weizhu; Dai, Jianxin; Zhao, Jian; Zhong, Yanqiang; Guo, Yajun

2009-05-01

The clinical use of Pseudomonas exotoxin A (PE)-based immunotoxins is limited by the toxicity and immunogenicity of PE. To overcome the limitations, we have developed PE38KDEL-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles conjugated with Fab' fragments of a humanized anti-HER2 monoclonal antibody (rhuMAbHER2). The PE38KDEL-loaded nanoparticles-anti-HER2 Fab' bioconjugates (PE-NP-HER) were constructed modularly with Fab' fragments of rhuMAbHER2 covalently linked to PLGA nanoparticles containing PE38KDEL. Compared with nontargeted nanoparticles that lack anti-HER2 Fab', PE-NP-HER specifically bound to and were sequentially internalized into HER2 overexpressing breast cancer cells, which result in significant cytotoxicity in vitro. In HER2 overexpressing tumor xenograft model system, administration of PE-NP-HER showed a superior efficacy in inhibiting tumor growth compared with PE-HER referring to PE38KDEL conjugated directly to rhuMAbHER2. Moreover, PE-NP-HER was well tolerated in mice with a higher LD(50) (LD(50) of 6.86 +/- 0.47 mg/kg vs. 2.21 +/- 0.32 mg/kg for PE-NP-HER vs. PE-HER (mean +/- SD); n = 3), and had no influence on the plasma level of plasma alanine aminotransferase (ALT) of animals when injected at a dose of 1 mg/kg where PE-HER caused significant increase of serum ALT in the treated mice. Notably, PE-NP-HER was of low immunogenicity in development of anti-PE38KDEL neutralizing antibodies and was less susceptible to inactivation by anti-PE38KDEL antibodies compared with PE-HER. This novel bioconjugate, PE-NP-HER, may represent a useful strategy for cancer treatment.

Update on testis tumours.

PubMed

Berney, Daniel M

2012-08-01

The range of testicular tumours is so large that many pathologists may encounter the rarer variants only a few times, if at all, in their career. This rarity and complexity results in immense challenges for pathologists. For clinicians, due to their rarity and the high cure rate, the difficulty in conducting randomised trials in this area, even in the more common germ cell tumours, means that progress is slow and it is difficult to accumulate evidence for the relevance of the various histopathological risk factors for recurrence. A number of recent trials and retrospective analyses have suggested that some histopathological features suggestive of recurrence are more important than others. This has implications both in how testicular tumours are examined macroscopically and microscopically. New clinically important entities will also be described, as well as some pitfalls in the diagnosis of testicular tumours and how to avoid them.

Therapeutic effect of apatinib-loaded nanoparticles on diabetes-induced retinal vascular leakage.

PubMed

Jeong, Ji Hoon; Nguyen, Hong Khanh; Lee, Jung Eun; Suh, Wonhee

2016-01-01

Apatinib, a novel and selective inhibitor of vascular endothelial growth factor (VEGF) receptor 2, has been demonstrated recently to exhibit anticancer efficacy by inhibiting the VEGF signaling pathway. Given the importance of VEGF in retinal vascular leakage, the present study was designed to investigate whether apatinib-loaded polymeric nanoparticles inhibit VEGF-mediated retinal vascular hyperpermeability and block diabetes-induced retinal vascular leakage. For the delivery of water-insoluble apatinib, the drug was encapsulated in nanoparticles composed of human serum albumin (HSA)-conjugated polyethylene glycol (PEG). In vitro paracellular permeability and transendothelial electric resistance assays showed that apatinib-loaded HSA-PEG (Apa-HSA-PEG) nanoparticles significantly inhibited VEGF-induced endothelial hyperpermeability in human retinal microvascular endothelial cells. In addition, they substantially reduced the VEGF-induced junctional loss and internalization of vascular endothelial-cadherin, a major component of endothelial junction complexes. In vivo intravitreal injection of Apa-HSA-PEG nanoparticles in mice blocked VEGF-induced retinal vascular leakage. These in vitro and in vivo data indicated that Apa-HSA-PEG nanoparticles efficiently blocked VEGF-induced breakdown of the blood-retinal barrier. In vivo experiments with streptozotocin-induced diabetic mice showed that an intravitreal injection of Apa-HSA-PEG nanoparticles substantially inhibited diabetes-induced retinal vascular leakage. These results demonstrated, for the first time, that apatinib-loaded nanoparticles may be a promising therapeutic agent for the prevention and treatment of diabetes-induced retinal vascular disorders.

Therapeutic effect of apatinib-loaded nanoparticles on diabetes-induced retinal vascular leakage

PubMed Central

Jeong, Ji Hoon; Nguyen, Hong Khanh; Lee, Jung Eun; Suh, Wonhee

2016-01-01

Apatinib, a novel and selective inhibitor of vascular endothelial growth factor (VEGF) receptor 2, has been demonstrated recently to exhibit anticancer efficacy by inhibiting the VEGF signaling pathway. Given the importance of VEGF in retinal vascular leakage, the present study was designed to investigate whether apatinib-loaded polymeric nanoparticles inhibit VEGF-mediated retinal vascular hyperpermeability and block diabetes-induced retinal vascular leakage. For the delivery of water-insoluble apatinib, the drug was encapsulated in nanoparticles composed of human serum albumin (HSA)-conjugated polyethylene glycol (PEG). In vitro paracellular permeability and transendothelial electric resistance assays showed that apatinib-loaded HSA-PEG (Apa-HSA-PEG) nanoparticles significantly inhibited VEGF-induced endothelial hyperpermeability in human retinal microvascular endothelial cells. In addition, they substantially reduced the VEGF-induced junctional loss and internalization of vascular endothelial-cadherin, a major component of endothelial junction complexes. In vivo intravitreal injection of Apa-HSA-PEG nanoparticles in mice blocked VEGF-induced retinal vascular leakage. These in vitro and in vivo data indicated that Apa-HSA-PEG nanoparticles efficiently blocked VEGF-induced breakdown of the blood–retinal barrier. In vivo experiments with streptozotocin-induced diabetic mice showed that an intravitreal injection of Apa-HSA-PEG nanoparticles substantially inhibited diabetes-induced retinal vascular leakage. These results demonstrated, for the first time, that apatinib-loaded nanoparticles may be a promising therapeutic agent for the prevention and treatment of diabetes-induced retinal vascular disorders. PMID:27462154

[Bellini tumours].

PubMed

Teghom, Corine; Gachet, Julie; Scotté, Florian; Elaidi, Reza; Oudard, Stéphane

2011-10-01

In Europe, renal tumours are 7th in frequency of men cancers. They are rare tumours in 10 to 15% of cases. Collecting ducts carcinomas or Bellini tumours, described for the first time in 1949, are a distinct clinical and pathological entity. They represented 1% of epithelial cancers. Nephrectomy is the treatment of localised cancer. Because of lack of recommendations, usually in clinical practice, treatment is similar to urothelial carcinomas treatments (gemcitabine plus platinium). A 72% of response rate of urothelial carcinoma to association of bevacizumab with platinium and gemcitabine 1st line chemotherapy in metastatic setting was reported. More, cases of responses of metastatic Bellini cancers to antiangiogenic treatments associated to chemotherapy were reported these last years. Bellini cancers have a poor prognostic. Unless the fact that this cancer is aggressive, after nephrectomy, cancer specific survival seems not to be different to those of patients with clear cells renal carcinoma and could be related to latest stage of disease in patients. The evaluation of efficacy of association of bevacizumab to chemotherapy is still going on in this association.

Gallic acid indanone and mangiferin xanthone are strong determinants of immunosuppressive anti-tumour effects of Mangifera indica L. bark in MDA-MB231 breast cancer cells.

PubMed

García-Rivera, Dagmar; Delgado, René; Bougarne, Nadia; Haegeman, Guy; Berghe, Wim Vanden

2011-06-01

Vimang is a standardized extract derived from Mango bark (Mangifera Indica L.), commonly used as anti-inflammatory phytomedicine, which has recently been used to complement cancer therapies in cancer patients. We have further investigated potential anti-tumour effects of glucosylxanthone mangiferin and indanone gallic acid, which are both present in Vimang extract. We observed significant anti-tumour effects of both Vimang constituents in the highly aggressive and metastatic breast cancer cell type MDA-MB231. At the molecular level, mangiferin and gallic acid both inhibit classical NFκB activation by IKKα/β kinases, which results in impaired IκB degradation, NFκB translocation and NFκB/DNA binding. In contrast to the xanthone mangiferin, gallic acid further inhibits additional NFκB pathways involved in cancer cell survival and therapy resistance, such as MEK1, JNK1/2, MSK1, and p90RSK. This results in combinatorial inhibition of NFκB activity by gallic acid, which results in potent inhibition of NFκB target genes involved in inflammation, metastasis, anti-apoptosis and angiogenesis, such as IL-6, IL-8, COX2, CXCR4, XIAP, bcl2, VEGF. The cumulative NFκB inhibition by gallic acid, but not mangiferin, is also reflected at the level of cell survival, which reveals significant tumour cytotoxic effects in MDA-MB231 cells. Altogether, we identify gallic acid, besides mangiferin, as an essential anti-cancer component in Vimang extract, which demonstrates multifocal inhibition of NFκB activity in the cancer-inflammation network. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling

PubMed Central

Ko, A; Kanehisa, A; Martins, I; Senovilla, L; Chargari, C; Dugue, D; Mariño, G; Kepp, O; Michaud, M; Perfettini, J-L; Kroemer, G; Deutsch, E

2014-01-01

Clinical oncology heavily relies on the use of radiotherapy, which often leads to merely transient responses that are followed by local or distant relapse. The molecular mechanisms explaining radioresistance are largely elusive. Here, we identified a dual role of autophagy in the response of cancer cells to ionizing radiation. On one hand, we observed that the depletion of essential autophagy-relevant gene products, such as ATG5 and Beclin 1, increased the sensitivity of human or mouse cancer cell lines to irradiation, both in vitro (where autophagy inhibition increased radiation-induced cell death and decreased clonogenic survival) and in vivo, after transplantation of the cell lines into immunodeficient mice (where autophagy inhibition potentiated the tumour growth-inhibitory effect of radiotherapy). On the other hand, when tumour proficient or deficient for autophagy were implanted in immunocompetent mice, it turned out that defective autophagy reduced the efficacy of radiotherapy. Indeed, radiotherapy elicited an anti-cancer immune response that was dependent on autophagy-induced ATP release from stressed or dying tumour cells and was characterized by dense lymphocyte infiltration of the tumour bed. Intratumoural injection of an ecto-ATPase inhibitor restored the immune infiltration of autophagy-deficient tumours post radiotherapy and improved the growth-inhibitory effect of ionizing irradiation. Altogether, our results reveal that beyond its cytoprotective function, autophagy confers immunogenic properties to tumours, hence amplifying the efficacy of radiotherapy in an immunocompetent context. This has far-reaching implications for the development of pharmacological radiosensitizers. PMID:24037090

TLR7 expression is decreased during tumour progression in transgenic adenocarcinoma of mouse prostate mice and its activation inhibits growth of prostate cancer cells.

PubMed

Han, Ju-Hee; Park, Shin-Young; Kim, Jin-Bum; Cho, Sung-Dae; Kim, Bumseok; Kim, Bo-Yeon; Kang, Min-Jung; Kim, Dong-Jae; Park, Jae-Hak; Park, Jong-Hwan

2013-10-01

Although various Toll-like receptors (TLRs) have been associated with immune response and tumorigenesis in the prostate cells, little is known about the role of TLR7. Accordingly, we examined the expression of TLR7 during tumour progression of TRMAP (transgenic mouse model for prostate cancer) mice and its role on cell growth. Toll-like receptor7 expression was examined by RT-polymerase chain reaction (PCR), Western blot, and immunohistochemistry. Cell growth was examined by MTT assay. Colony formation was investigated by crystal violet staining. Strong expression of TLR7 was detected in the normal prostate epithelia of Wild-type (WT) mice, but not in TLR7-deficient mice. In contrast, TLR7 expression was weak in transgenic adenocarcinoma of mouse prostate (TRAMP)-C2 cells, as compared with murine bone marrow-derived macrophages (BMDMs). Moreover, TLR7 mRNA was markedly expressed in RWPE-1 cells (non-cancerous prostate epithelial cells), but not in PC3 and DU145 (prostate cancer cells). Immunohistochemically, TLR7 expression gradually decreased in TRAMP mice depending on the pathologic grade of the prostate cells. TLR7 agonists increased both the gene and protein expression of TLR7 and promoted production of proinflammatory cytokines/chemokines and IFN-β gene expression in prostate cancer cell lines. Moreover, loxoribine inhibited the growth and colony formation of TRAMP-C2 cells dependent of TLR7. These findings suggest that TLR7 may participate in tumour suppression in the prostate cells. © 2013 John Wiley & Sons Ltd.

Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy

NASA Astrophysics Data System (ADS)

He, Chunbai; Duan, Xiaopin; Guo, Nining; Chan, Christina; Poon, Christopher; Weichselbaum, Ralph R.; Lin, Wenbin

2016-08-01

Advanced colorectal cancer is one of the deadliest cancers, with a 5-year survival rate of only 12% for patients with the metastatic disease. Checkpoint inhibitors, such as the antibodies inhibiting the PD-1/PD-L1 axis, are among the most promising immunotherapies for patients with advanced colon cancer, but their durable response rate remains low. We herein report the use of immunogenic nanoparticles to augment the antitumour efficacy of PD-L1 antibody-mediated cancer immunotherapy. Nanoscale coordination polymer (NCP) core-shell nanoparticles carry oxaliplatin in the core and the photosensitizer pyropheophorbide-lipid conjugate (pyrolipid) in the shell (NCP@pyrolipid) for effective chemotherapy and photodynamic therapy (PDT). Synergy between oxaliplatin and pyrolipid-induced PDT kills tumour cells and provokes an immune response, resulting in calreticulin exposure on the cell surface, antitumour vaccination and an abscopal effect. When combined with anti-PD-L1 therapy, NCP@pyrolipid mediates regression of both light-irradiated primary tumours and non-irradiated distant tumours by inducing a strong tumour-specific immune response.

Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism

NASA Astrophysics Data System (ADS)

Cagno, Valeria; Andreozzi, Patrizia; D'Alicarnasso, Marco; Jacob Silva, Paulo; Mueller, Marie; Galloux, Marie; Le Goffic, Ronan; Jones, Samuel T.; Vallino, Marta; Hodek, Jan; Weber, Jan; Sen, Soumyo; Janeček, Emma-Rose; Bekdemir, Ahmet; Sanavio, Barbara; Martinelli, Chiara; Donalisio, Manuela; Rameix Welti, Marie-Anne; Eleouet, Jean-Francois; Han, Yanxiao; Kaiser, Laurent; Vukovic, Lela; Tapparel, Caroline; Král, Petr; Krol, Silke; Lembo, David; Stellacci, Francesco

2018-02-01

Viral infections kill millions yearly. Available antiviral drugs are virus-specific and active against a limited panel of human pathogens. There are broad-spectrum substances that prevent the first step of virus-cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them. We designed antiviral nanoparticles with long and flexible linkers mimicking HSPG, allowing for effective viral association with a binding that we simulate to be strong and multivalent to the VAL repeating units, generating forces (~190 pN) that eventually lead to irreversible viral deformation. Virucidal assays, electron microscopy images, and molecular dynamics simulations support the proposed mechanism. These particles show no cytotoxicity, and in vitro nanomolar irreversible activity against herpes simplex virus (HSV), human papilloma virus, respiratory syncytial virus (RSV), dengue and lenti virus. They are active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV.

FAK-heterozygous mice display enhanced tumour angiogenesis

PubMed Central

Kostourou, Vassiliki; Lechertier, Tanguy; Reynolds, Louise E.; Lees, Delphine M.; Baker, Marianne; Jones, Dylan T.; Tavora, Bernardo; Ramjaun, Antoine R.; Birdsey, Graeme M.; Robinson, Stephen D.; Parsons, Maddy; Randi, Anna M.; Hart, Ian R; Hodivala-Dilke, Kairbaan

2013-01-01

Genetic ablation of endothelial Focal Adhesion Kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularisation. Here we show that reduced stromal-FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumor growth in vivo. Our results highlight a potential novel role for FAK as a non-linear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis. PMID:23799510

Differential Patterns of Vasculature to Liver Tumours

PubMed Central

Assa, J.

1970-01-01

An angiographic study of the vasculature of Vx2 tumour deposits in the rabbit's liver is described. Tumours transplanted from donor rabbits within less than 2 weeks incubation, developed into an amorphic infiltrating tumour, characterized by a rich arterial network. Tumours harvested after 3 weeks growth in donors, became cystic and had a scanty arterial supply. In both groups there was no portal circulation to the tumours' deposits. It is suggested that prior to intra-arterial treatment of cancer in the liver, the morphology of the tumour should be assessed. ImagesFigs. 3-4Figs. 5-6Figs. 7-8Figs. 1-2 PMID:5451574

Pitfalls in colour photography of choroidal tumours

PubMed Central

Schalenbourg, A; Zografos, L

2013-01-01

Colour imaging of fundus tumours has been transformed by the development of digital and confocal scanning laser photography. These advances provide numerous benefits, such as panoramic images, increased contrast, non-contact wide-angle imaging, non-mydriatic photography, and simultaneous angiography. False tumour colour representation can, however, cause serious diagnostic errors. Large choroidal tumours can be totally invisible on angiography. Pseudogrowth can occur because of artefacts caused by different methods of fundus illumination, movement of reference blood vessels, and flattening of Bruch's membrane and sclera when tumour regression occurs. Awareness of these pitfalls should prevent the clinician from misdiagnosing tumours and wrongfully concluding that a tumour has grown. PMID:23238442

Pitfalls in colour photography of choroidal tumours.

PubMed

Schalenbourg, A; Zografos, L

2013-02-01

Colour imaging of fundus tumours has been transformed by the development of digital and confocal scanning laser photography. These advances provide numerous benefits, such as panoramic images, increased contrast, non-contact wide-angle imaging, non-mydriatic photography, and simultaneous angiography. False tumour colour representation can, however, cause serious diagnostic errors. Large choroidal tumours can be totally invisible on angiography. Pseudogrowth can occur because of artefacts caused by different methods of fundus illumination, movement of reference blood vessels, and flattening of Bruch's membrane and sclera when tumour regression occurs. Awareness of these pitfalls should prevent the clinician from misdiagnosing tumours and wrongfully concluding that a tumour has grown.

Nanoparticle therapeutics: Technologies and methods for overcoming cancer.

PubMed

Cerqueira, Brenda Brenner S; Lasham, Annette; Shelling, Andrew N; Al-Kassas, Raida

2015-11-01

It is anticipated that by 2030 approximately 13 million people will die of cancer. Common cancer therapy often fails due to the development of multidrug resistance (MDR), resulting in high morbidity and poor patient prognosis. Nanotechnology seeks to use drug delivery vehicles of 1-100 nm in diameter, made up of several different materials to deliver anti-cancer drugs selectively to cancer cells and potentially overcome MDR. Several technologies exist for manufacturing and functionalizing nanoparticles. When functionalized appropriately, nanoparticles have been shown to overcome several mechanisms of MDR in vivo and in vitro, reduce drug side effects and represent a promising new area of anti-cancer therapy. This review discusses the fundamental concepts of enhanced permeability and retention (EPR) effect and explores the mechanisms proposed to enhance preferential "retention" in the tumour. The overall objective of this review was to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancer. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

Modulating chromatin structure and DNA accessibility by deacetylase inhibition enhances the anti-cancer activity of silver nanoparticles.

PubMed

Igaz, Nóra; Kovács, Dávid; Rázga, Zsolt; Kónya, Zoltán; Boros, Imre M; Kiricsi, Mónika

2016-10-01

Histone deacetylase (HDAC) inhibitors are considered as novel therapeutic agents inducing cell cycle arrest and apoptotic cell death in various cancer cells. Inhibition of deacetylase activity results in a relaxed chromatin structure thereby rendering the genetic material more vulnerable to DNA targeting agents that could be exploited by combinational cancer therapy. The unique potential of silver nanoparticles (AgNPs) in tumor therapy relies on the generation of reactive radicals which trigger oxidative stress, DNA damage and apoptosis in cancer cells. The revolutionary application of AgNPs as chemotherapeutical drugs seems very promising, nevertheless the exact molecular mechanisms of AgNP action in combination with other anti-cancer agents have yet to be elucidated in details before clinical administrations. As a step towards this we investigated the combinational effect of HDAC inhibition and AgNP administration in HeLa cervical cancer cells. We identified synergistic inhibition of cancer cell growth and migration upon combinational treatments. Here we report that the HDAC inhibitor Trichostatin A enhances the DNA targeting capacity and apoptosis inducing efficacy of AgNPs most probably due to its effect on chromatin condensation. These results point to the potential benefits of combinational application of HDAC inhibitors and AgNPs in novel cancer medication protocols. Copyright © 2016 Elsevier B.V. All rights reserved.

Overcoming resistance to molecularly targeted anticancer therapies: rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies

PubMed Central

Tortora, Giampaolo; Bianco, Roberto; Daniele, Gennaro; Ciardiello, Fortunato; McCubrey, James A; Ricciardi, Maria Rosaria; Ciuffreda, Ludovica; Cognetti, Francesco; Tafuri, Agostino; Milella, Michele

2007-01-01

Accumulating evidence suggests that cancer can be envisioned as a “signaling disease”, in which alterations in the cellular genome affect the expression and/or function of oncogenes and tumour suppressor genes. This ultimately disrupts the physiologic transmission of biochemical signals that normally regulate cell growth, differentiation and programmed cell death (apoptosis). From a clinical standpoint, signal transduction inhibition as a therapeutic strategy for human malignancies has recently achieved remarkable success. However, as additional drugs move forward into the clinical arena, intrinsic and acquired resistance to “targeted” agents becomes an issue for their clinical utility. One way to overcome resistance to targeted agents is to identify genetic and epigenetic aberrations underlying sensitivity/resistance, thus enabling the selection of patients that will most likely benefit from a specific therapy. Since resistance often ensues as a result of the concomitant activation of multiple, often overlapping, signaling pathways, another possibility is to interfere with multiple, cross-talking pathways involved in growth and survival control in a rational, mechanism-based, fashion. These concepts may be usefully applied, among others, to agents that target two major signal transduction pathways: the one initiated by epidermal growth factor receptor (EGFR) signaling and the one converging on mitogen-activated protein kinase (MAPK) activation. Here we review the molecular mechanisms of sensitivity/resistance to EGFR inhibitors, as well as the rationale for combining them with other targeted agents, in an attempt to overcome resistance. In the second part of the paper, we review MAPK-targeted agents, focusing on their therapeutic potential in hematologic malignancies, and examine the prospects for combinations of MAPK inhibitors with cytotoxic agents or other signal transduction-targeted agents to obtain synergistic anti-tumour effects. PMID:17482503

Histopathology of malignant salivary gland tumours.

PubMed

Seifert, G

1992-07-01

This report is based upon the Salivary Gland Register in Hamburg and on the second revised edition of the WHO Histological Typing of Salivary Gland Tumours. The group of malignant salivary gland tumours contains carcinomas, malignant non-epithelial tumours, malignant lymphomas and secondary tumours. The various carcinomas are classified in a continuous separate listing because the different types are distinguished not only by histopathology, but also by differences in prognosis and treatment. The term "tumour" is replaced by "carcinoma" in two entities: acinic cell carcinoma and mucoepidermoid carcinoma. New entities are: polymorphous low-grade adenocarcinoma, basal cell adenocarcinoma, salivary duct carcinoma and malignant myoepithelioma. Carcinoma in pleomorphic adenoma can be distinguished as non-invasive and invasive carcinoma, and carcinosarcoma. Malignant non-epithelial tumours are mostly malignant fibrous histiocytoma, malignant schwannoma and rhabdomyosarcoma. The large majority of malignant lymphomas are non-Hodgkin-lymphomas with high differentiation. Many lymphomas are associated with chronic immunosialadenitis (Sjögren's syndrome). Secondary tumours are mostly metastases from primary squamous cell carcinomas or from melanomas of the skin (head and neck area). Haematogeneous metastases are very rare (mainly from lung, kidney or breast).

How can macromolecular crowding inhibit biological reactions? The enhanced formation of DNA nanoparticles

PubMed Central

Hou, Sen; Trochimczyk, Piotr; Sun, Lili; Wisniewska, Agnieszka; Kalwarczyk, Tomasz; Zhang, Xuzhu; Wielgus-Kutrowska, Beata; Bzowska, Agnieszka; Holyst, Robert

2016-01-01

In contrast to the already known effect that macromolecular crowding usually promotes biological reactions, solutions of PEG 6k at high concentrations stop the cleavage of DNA by HindIII enzyme, due to the formation of DNA nanoparticles. We characterized the DNA nanoparticles and probed the prerequisites for their formation using multiple techniques such as fluorescence correlation spectroscopy, dynamic light scattering, fluorescence analytical ultracentrifugation etc. In >25% PEG 6k solution, macromolecular crowding promotes the formation of DNA nanoparticles with dimensions of several hundreds of nanometers. The formation of DNA nanoparticles is a fast and reversible process. Both plasmid DNA (2686 bp) and double-stranded/single-stranded DNA fragment (66bp/nt) can form nanoparticles. We attribute the enhanced nanoparticle formation to the depletion effect of macromolecular crowding. This study presents our idea to enhance the formation of DNA nanoparticles by macromolecular crowding, providing the first step towards a final solution to efficient gene therapy. PMID:26903405

How can macromolecular crowding inhibit biological reactions? The enhanced formation of DNA nanoparticles.

PubMed

Hou, Sen; Trochimczyk, Piotr; Sun, Lili; Wisniewska, Agnieszka; Kalwarczyk, Tomasz; Zhang, Xuzhu; Wielgus-Kutrowska, Beata; Bzowska, Agnieszka; Holyst, Robert

2016-02-23

In contrast to the already known effect that macromolecular crowding usually promotes biological reactions, solutions of PEG 6k at high concentrations stop the cleavage of DNA by HindIII enzyme, due to the formation of DNA nanoparticles. We characterized the DNA nanoparticles and probed the prerequisites for their formation using multiple techniques such as fluorescence correlation spectroscopy, dynamic light scattering, fluorescence analytical ultracentrifugation etc. In >25% PEG 6k solution, macromolecular crowding promotes the formation of DNA nanoparticles with dimensions of several hundreds of nanometers. The formation of DNA nanoparticles is a fast and reversible process. Both plasmid DNA (2686 bp) and double-stranded/single-stranded DNA fragment (66 bp/nt) can form nanoparticles. We attribute the enhanced nanoparticle formation to the depletion effect of macromolecular crowding. This study presents our idea to enhance the formation of DNA nanoparticles by macromolecular crowding, providing the first step towards a final solution to efficient gene therapy.

Molecular profiling of tumour budding implicates TGFβ-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma.

PubMed

Jensen, D H; Dabelsteen, E; Specht, L; Fiehn, A M K; Therkildsen, M H; Jønson, L; Vikesaa, J; Nielsen, F C; von Buchwald, C

2015-08-01

Although tumour budding is an adverse prognostic factor for many cancer types, the molecular mechanisms governing this phenomenon are incompletely understood. Therefore, understanding the molecular basis of tumour budding may provide new therapeutic and diagnostic options. We employ digital image analysis to demonstrate that the number of tumour buds in cytokeratin-stained sections correlates with patients having lymph node metastases at diagnosis. The tumour bud count was also a predictor of overall survival, independent of TNM stage. Tumour buds and paired central tumour areas were subsequently collected from oral squamous cell carcinoma (OSCC) specimens, using laser capture microdissection, and examined with RNA sequencing and miRNA-qPCR arrays. Compared with cells from the central parts of the tumours, budding cells exhibited a particular gene expression signature, comprising factors involved in epithelial-mesenchymal transition (EMT) and activated TGFβ signalling. Transcription factors ZEB1 and PRRX1 were up-regulated concomitantly with the decreased expression of mesenchymal-epithelial (MET) transcription factors (eg OVOL1) in addition to Krüppel-like factors and Grainyhead-like factors. Moreover, miR-200 family members were down-regulated in budding tumour cells. We used immunohistochemistry to validate five markers of the EMT/MET process in 199 OSCC tumours, as well as in situ hybridization in 20 OSCC samples. Given the strong relationship between tumour budding and the development of lymph node metastases and an adverse prognosis, therapeutics based on inhibiting the activation of TGFβ signalling may prove useful in the treatment of OSCC. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Neutrophil-mediated experimental metastasis is enhanced by VEGFR inhibition in a zebrafish xenograft model

PubMed Central

He, Shuning; Lamers, Gerda EM; Beenakker, Jan-Willem M; Cui, Chao; Ghotra, Veerander PS; Danen, Erik HJ; Meijer, Annemarie H; Spaink, Herman P; Snaar-Jagalska, B Ewa

2012-01-01

Inhibition of VEGF signalling effectively suppresses localized tumour growth but accelerates tumour invasiveness and micrometastasis by unknown mechanisms. To study the dynamic and reciprocal interactions between tumour cells and their microenvironment during these processes, we established a xenograft model by injecting tumour cells into the blood circulation of transparent zebrafish embryos. This reproducibly results in rapid simultaneous formation of a localized tumour and experimental micrometastasis, allowing time-resolved imaging of both processes at single-cell resolution within 1 week. The tumour vasculature was initiated de novo by remodelling of primitive endothelial cells into a functional network. Roles of myeloid cells in critical tumourigenesis steps such as vascularization and invasion were revealed by genetic and pharmaceutical approaches. We discovered that the physiological migration of neutrophils controlled tumour invasion by conditioning the collagen matrix and forming the metastatic niche, as detected by two-photon confocal microscopy and second harmonic generation. Administration of VEGFR inhibitors blocked tumour vascularization and a localized tumour growth but enhanced migration of neutrophils, which in turn promoted tumour invasion and formation of micrometastasis. This demonstrates the in vivo cooperation between VEGF signalling and myeloid cells in metastasis and provides a new mechanism underlying the recent findings that VEGFR targeting can promote tumour invasiveness. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:22374800

Solitary fibrous tumour of the cheek: An unusual presentation of a rare soft tissue tumour

PubMed Central

Jones, JL; Jones, AV; Drage, NA; Bhatia, S; Hourihan, MD

2014-01-01

This case report discusses the unusual presentation and ultrasound features of a solitary fibrous tumour of the face. Solitary fibrous tumour is an uncommon form of soft tissue tumour which, although seen predominantly within the lung pleura, can occur throughout the body in sites such as the peritoneum, mediastinum and head and neck. Ultrasound is an excellent imaging modality in the assessment of soft tissue masses in the head and neck. The ultrasound features demonstrated by this example of solitary fibrous tumour are reviewed. This report also highlights that ultrasound alone is ultimately limited in reaching a definitive diagnosis. The roles of other investigations such as ultrasound-guided biopsy and cross-sectional imaging are discussed. PMID:27433225

Effects of nandrolone decanoate on the toxicity and anti-tumour action of CCNU and FU in murine tumours.

PubMed Central

Bibby, M. C.; Double, J. A.; Mughal, M. A.

1981-01-01

Pre-treatment with the anabolic steroid nandrolone decanoate (ND) increases the LD50 of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 5-Fluorouracil (FU) in NMRI mice. Administration of ND did not affect the anti-tumour action of CCNU against a transplantable mouse adenocarcinoma of the colon (MAC 13) or the anti-tumour action of FU against MAC 26. In both tumour lines ND had no significant effect on tumour growth. These data suggest that an increase in the anti-tumour selectivity of these agents may be produced by pre-treatment with ND. PMID:7295514

Influence of femtosecond laser radiation on cells of the transplantable tumour Krebs-2

NASA Astrophysics Data System (ADS)

Meshalkin, Yu P.; Popova, N. A.; Nikolin, V. P.; Kaledin, V. I.; Kirpichnikov, A. V.; Pestryakov, Efim V.

2012-06-01

The influence of femtosecond radiation of a titaniumsapphire laser on cells of the transplantable ascitic tumour Krebs-2 was studied. After in vitro irradiation by the pulsed fundamentalharmonic radiation with the wavelength 800 nm, pulse duration 30 fs, repetition rate 1 kHz, mean power 100 and 300 mW and exposure time 3 min, as well as by the second-harmonic radiation (40 nm, 50 fs, 120 mW), all cells were diffusely stained by the vital stain trypan blue, which may be an evidence of their death or abnormalities of membrane permeability. However, implantation of such cells to experimental animals led to formation of tumours at the transplantation site with the kinetics slightly different from the control one. In the group of mice to which the cells were inoculated after irradiation with second harmonic pulses of titanium-sapphire laser the inhibition of tumour growth was observed due to partial death of cells under the action of UV spectral components. To explain the mechanism of the observed phenomenon the possibility of pore formation (photoporation) in the cell membrane, described earlier in the papers on foreign DNA transfection into cells, is considered.

Naturally occurring tumours in the basal metazoan Hydra.

PubMed

Domazet-Lošo, Tomislav; Klimovich, Alexander; Anokhin, Boris; Anton-Erxleben, Friederike; Hamm, Mailin J; Lange, Christina; Bosch, Thomas C G

2014-06-24

The molecular nature of tumours is well studied in vertebrates, although their evolutionary origin remains unknown. In particular, there is no evidence for naturally occurring tumours in pre-bilaterian animals, such as sponges and cnidarians. This is somewhat surprising given that recent computational studies have predicted that most metazoans might be prone to develop tumours. Here we provide first evidence for naturally occurring tumours in two species of Hydra. Histological, cellular and molecular data reveal that these tumours are transplantable and might originate by differentiation arrest of female gametes. Growth of tumour cells is independent from the cellular environment. Tumour-bearing polyps have significantly reduced fitness. In addition, Hydra tumours show a greatly altered transcriptome that mimics expression shifts in vertebrate cancers. Therefore, this study shows that spontaneous tumours have deep evolutionary roots and that early branching animals may be informative in revealing the fundamental mechanisms of tumorigenesis.

Inhibition of cyclooxygenase (COX)-2 affects endothelial progenitor cell proliferation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colleselli, Daniela; Bijuklic, Klaudija; Mosheimer, Birgit A.

2006-09-10

Growing evidence indicates that inducible cyclooxygenase-2 (COX-2) is involved in the pathogenesis of inflammatory disorders and various types of cancer. Endothelial progenitor cells recruited from the bone marrow have been shown to be involved in the formation of new vessels in malignancies and discussed for being a key point in tumour progression and metastasis. However, until now, nothing is known about an interaction between COX and endothelial progenitor cells (EPC). Expression of COX-1 and COX-2 was detected by semiquantitative RT-PCR and Western blot. Proliferation kinetics, cell cycle distribution and rate of apoptosis were analysed by MTT test and FACS analysis.more » Further analyses revealed an implication of Akt phosphorylation and caspase-3 activation. Both COX-1 and COX-2 expression can be found in bone-marrow-derived endothelial progenitor cells in vitro. COX-2 inhibition leads to a significant reduction in proliferation of endothelial progenitor cells by an increase in apoptosis and cell cycle arrest. COX-2 inhibition leads further to an increased cleavage of caspase-3 protein and inversely to inhibition of Akt activation. Highly proliferating endothelial progenitor cells can be targeted by selective COX-2 inhibition in vitro. These results indicate that upcoming therapy strategies in cancer patients targeting COX-2 may be effective in inhibiting tumour vasculogenesis as well as angiogenic processes.« less

Green synthesis of Ag nanoparticles for water treatment (antimicrobial on Eschirichia coli)

NASA Astrophysics Data System (ADS)

Darus, Mazlina Mat; Mahusin, Wan Norazwani

2017-05-01

Green synthesis approach was used to synthesis silver (Ag) nanoparticles. In this study, a one-step method was employed via hydrothermal technique. Samples are synthesized at different temperatures and times. All samples were characterized by Field Emission Scanning Electron Microscopy (FESEM). The morphology of the as-synthesized Ag samples are consists of nanoparticles and nanoplates with the diameter is in the range of 45 - 140 nm. The Ag nanoparticles were tested on Gram-Negative bacteria, Eschirichia coli (E.coli) which represent as an indicator for water pollution by using disc diffusion methods. Different concentrations of Ag nanoparticles were used to treat E.coli which is at 25 µg/ml, 50 µg/ml and 100 µg/ml respectively. The results show that for every samples, the inhibition zone of the E.coli increased as the concentration of Ag nanoparticles increased. Ag nanoparticles which synthesized at 100 °C/ 8 hrs exhibits the most optimum inhibition zone for the growth of E.coli due to its smaller size and the triangular nanoplate shaped. The diameter of the inhibition zone is between 6.17 ± 0.03 to 8.03 ± 0.03 mm.

CNS embryonal tumours: WHO 2016 and beyond.

PubMed

Pickles, J C; Hawkins, C; Pietsch, T; Jacques, T S

2018-02-01

Embryonal tumours of the central nervous system (CNS) present a significant clinical challenge. Many of these neoplasms affect young children, have a very high mortality and therapeutic strategies are often aggressive with poor long-term outcomes. There is a great need to accurately diagnose embryonal tumours, predict their outcome and adapt therapy to the individual patient's risk. For the first time in 2016, the WHO classification took into account molecular characteristics for the diagnosis of CNS tumours. This integration of histological features with genetic information has significantly changed the diagnostic work-up and reporting of tumours of the CNS. However, this remains challenging in embryonal tumours due to their previously unaccounted tumour heterogeneity. We describe the recent revisions made to the 4th edition of the WHO classification of CNS tumours and review the main changes, while highlighting some of the more common diagnostic testing strategies. © 2017 British Neuropathological Society.

Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles

NASA Astrophysics Data System (ADS)

Kishimoto, Takashi K.; Ferrari, Joseph D.; Lamothe, Robert A.; Kolte, Pallavi N.; Griset, Aaron P.; O'Neil, Conlin; Chan, Victor; Browning, Erica; Chalishazar, Aditi; Kuhlman, William; Fu, Fen-Ni; Viseux, Nelly; Altreuter, David H.; Johnston, Lloyd; Maldonado, Roberto

2016-10-01

The development of antidrug antibodies (ADAs) is a common cause for the failure of biotherapeutic treatments and adverse hypersensitivity reactions. Here we demonstrate that poly(lactic-co-glycolic acid) (PLGA) nanoparticles carrying rapamycin, but not free rapamycin, are capable of inducing durable immunological tolerance to co-administered proteins that is characterized by the induction of tolerogenic dendritic cells, an increase in regulatory T cells, a reduction in B cell activation and germinal centre formation, and the inhibition of antigen-specific hypersensitivity reactions. Intravenous co-administration of tolerogenic nanoparticles with pegylated uricase inhibited the formation of ADAs in mice and non-human primates and normalized serum uric acid levels in uricase-deficient mice. Similarly, the subcutaneous co-administration of nanoparticles with adalimumab resulted in the durable inhibition of ADAs, leading to normalized pharmacokinetics of the anti-TNFα antibody and protection against arthritis in TNFα transgenic mice. Adjunct therapy with tolerogenic nanoparticles represents a novel and broadly applicable approach to prevent the formation of ADAs against biologic therapies.

Conatumumab (AMG 655) coated nanoparticles for targeted pro-apoptotic drug delivery.

PubMed

Fay, Francois; McLaughlin, Kirsty M; Small, Donna M; Fennell, Dean A; Johnston, Patrick G; Longley, Daniel B; Scott, Christopher J

2011-11-01

Colloidal nanoparticle drug delivery systems have attracted much interest for their ability to enable effective formulation and delivery of therapeutic agents. The selective delivery of these nanoparticles to the disease site can be enhanced by coating the surface of the nanoparticles with targeting moieties, such as antibodies. In this current work, we demonstrate that antibodies on the surface of the particles can also elicit key biological effects. Specifically, we demonstrate the induction of apoptosis in colorectal HCT116 cancer cells using PLGA nanoparticles coated with Conatumumab (AMG 655) death receptor 5-specific antibodies (DR5-NP). We show that DR5-NP preferentially target DR5-expressing cells and present a sufficient density of antibody paratopes to induce apoptosis via DR5, unlike free AMG 655 or non-targeted control nanoparticles. We also demonstrate that DR5-targeted nanoparticles encapsulating the cytotoxic drug camptothecin are effectively targeted to the tumour cells, thereby producing enhanced cytotoxic effects through simultaneous drug delivery and apoptosis induction. These results demonstrate that antibodies on nanoparticulate surfaces can be exploited for dual modes of action to enhance the therapeutic utility of the modality. Copyright © 2011 Elsevier Ltd. All rights reserved.

Biosynthesis of silver nanoparticles using Sida acuta extract for antimicrobial actions and corrosion inhibition potential.

PubMed

Idrees, Muhammad; Batool, Saima; Kalsoom, Tanzila; Raina, Sadaf; Sharif, Hafiz Muhammad Adeel; Yasmeen, Summera

2018-02-12

Nanotechnology exhibits a multidisciplinary area and gained interests for researchers. Nanoparticles produced via physical and chemical methods affects ecosystem drastically. Green synthesis is the charming technique that is inexpensive and safe for the environment. This study aimed to explore the antibacterial actions of as-synthesized silver nanoparticles (Ag-NPs) against Escherichia coli, Staphylococcus aureus and Streptococcus faecalis. Also, the anti-corrosion actions confirmed that the Ag-NPs proved as good inhibitors. In this way, Ag-NPs were prepared via biosynthesis technique by consuming the ground leaves and stem of 'Sida acuta' as a capping agent. The Ag-NPs were formed by irradiation of the aqueous solution of silver nitrate (AgNO 3 ) with extract of S. acuta stem and leaves. The as-synthesized reaction mixture of Ag-NPs was found to exhibit an absorbance band at 446-447 nm, by an UV/VIS spectrophotometer, which is a characteristic of Ag-NPs due to the surface plasmon resonance absorption band. The X-ray diffraction and transmission electron microscopy (TEM) were used for the confirmation of Ag-NPs' variety dimension, morphology and dispersion. The infrared spectra confirmed the bio-fabrication of the Ag-NPs displayed the existence of conceivable functional groups responsible for the bio-reduction and capping. The antimicrobial actions were measured and the zone of inhibition was compared with standard antibiotics.

Relationship of serum CEA levels to tumour size and CEA content in nude mice bearing colonic-tumour xenografts.

PubMed Central

Lewis, J. C.; Keep, P. A.

1981-01-01

The relationship of serum carcinoembryonic antigen (CEA) levels to tumour size and antigen content was studied in nude mice bearing well differentiated, mucinous human colonic-tumour xenografts. Blood samples were taken from normal nude mice and others bearing xenografts, whose size had been calculated from in vivo measurements; saline and KCl extracts were made of a proportion of these tumours. Sera and tissue extracts were assayed for CEA activity by double-antibody radioimmunoassay. Extracts were also made from the livers and spleens of tumour-bearing and normal nude mice. All normal sera and 78% of sera from tumour-bearing animals had CEA values less than 11.4 ng/ml. No clear correlation was found between serum CEA levels greater than 11.4 ng/ml and tumour size or weight, or between serum CEA and tumour CEA concentrations or total CEA burden. The concentration of CEA in those tumours tested varied from 1 to 22 microgram/g. Our results confirm and extend the conclusions reached by others (Stragand et al., 1980) studying the significance of serum CEA levels with xenograft model systems. The complexity of factors contributing to circulating CEA is discussed in the light of our findings. Images Fig. 1 PMID:7284235

The PP4R1 sub-unit of protein phosphatase PP4 is essential for inhibition of NF-κB by merkel polyomavirus small tumour antigen.

PubMed

Abdul-Sada, Hussein; Müller, Marietta; Mehta, Rajni; Toth, Rachel; Arthur, J Simon C; Whitehouse, Adrian; Macdonald, Andrew

2017-04-11

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with a high metastatic potential. The majority of MCC cases are caused by the Merkel cell polyomavirus (MCPyV), through expression of the virus-encoded tumour antigens. Whilst mechanisms attributing tumour antigen expression to transformation are being uncovered, little is known of the mechanisms by which MCPyV persists in the host. We previously identified the MCPyV small T antigen (tAg) as a novel inhibitor of nuclear factor kappa B (NF-kB) signalling and a modulator of the host anti-viral response. Here we demonstrate that regulation of NF-kB activation involves a previously undocumented interaction between tAg and regulatory sub-unit 1 of protein phosphatase 4 (PP4R1). Formation of a complex with PP4R1 and PP4c is required to bridge MCPyV tAg to the NEMO adaptor protein, allowing deactivation of the NF-kB pathway. Mutations in MCPyV tAg that fail to interact with components of this complex, or siRNA depletion of PP4R1, prevents tAg-mediated inhibition of NF-kB and pro-inflammatory cytokine production. Comparison of tAg binding partners from other human polyomavirus demonstrates that interactions with NEMO and PP4R1 are unique to MCPyV. Collectively, these data identify PP4R1 as a novel target for virus subversion of the host anti-viral response.

Anti-tumour potential of a gallic acid-containing phenolic fraction from Oenothera biennis.

PubMed

Pellegrina, Chiara Dalla; Padovani, Giorgia; Mainente, Federica; Zoccatelli, Gianni; Bissoli, Gaetano; Mosconi, Silvia; Veneri, Gianluca; Peruffo, Angelo; Andrighetto, Giancarlo; Rizzi, Corrado; Chignola, Roberto

2005-08-08

A phenolic fraction purified form defatted seeds of Oenothera biennis promoted selective apoptosis of human and mouse bone marrow-derived cell lines following first-order kinetics through a caspase-dependent pathway. In non-leukemia tumour cell lines, such as human colon carcinoma CaCo(2) cells and mouse fibrosarcoma WEHI164 cells, this fraction inhibited (3)H-thymidine incorporation but not cell death or cell cycle arrest. Human peripheral blood mononuclear cells showed low sensitivity to treatment. Single bolus injection of the phenolic fraction could delay the growth of established myeloma tumours in syngeneic animals. HPLC and mass spectrometry analysis revealed that the fraction contains gallic acid. However, the biological activity of the fraction differs from the activity of this phenol and hence it should be attributed to other co-purified molecules which remain still unidentified.

Pancreatic tumours produce neurotensin.

PubMed

Blackburn, A M; Bryant, M G; Adrian, T E; Bloom, S R

1981-04-01

Tumour tissue may secrete substances which are not normally secreted by the original tissue. We have found that 6 out of 21 pancreatic tumours producing vasoactive intestinal peptide also produce neurotensin-like peptides. These are sometimes secreted and very high plasma levels of neurotensin-like immunoreactivity may be found in the circulation.