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Tumor resistence

Feng-Yang Wang, Xiao-Ming Tang, Xia Wang, Ke-Bin Huang, Hai-Wen Feng, Zhen-Feng Chen, You-Nian Liu, Hong Liang
Agents with multiple modes of tumor cell death can be effective chemotherapeutic drugs. One example of a bimodal chemotherapeutic approach is an agent that can induce both apoptosis and autophagic death. Thus far, no clinical anticancer drug has been shown to simultaneously induce both these pathways. Mono-functional platinum complexes are potent anticancer drug candidates which act through mechanisms distinct from cisplatin. Here, we describe the synthesis and characterize of two mono-functional platinum complexes containing 8-substituted quinoline derivatives as ligands, [PtL1 Cl]Cl [L1  = (Z)-1-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) methanamine] (Mon-Pt-1) and [PtL2 Cl]Cl [L2  = (Z)-2-(pyridin-2-yl)-N-(quinolin-8-ylmethylene) ethanamine] (Mon-Pt-2)...
June 9, 2018: European Journal of Medicinal Chemistry
Michael P Shea, Kathleen A O'Leary, Kyle A Wegner, Chad M Vezina, Linda A Schuler
Metastatic estrogen receptor alpha positive (ERα+) cancers account for most breast cancer mortality. Cancer stem cells (CSCs) and dense/stiff extracellular matrices are implicated in aggression and therapy resistance. We examined this interplay and response to mTOR inhibition using ERα+ adenocarcinomas from NRL-PRL females in combination with Col1a1tmJae/+ (mCol1a1) mice, which accumulate collagen-I around growing tumors. Orthotopic transplantation of tumor cells to mCol1a1 but not wildtype hosts resulted in striking desmoplasia...
June 20, 2018: Cancer Letters
Charline Ogier, Pierre-Emmanuel Colombo, Corinne Bousquet, Lucile Canterel-Thouennon, Pierre Sicard, Véronique Garambois, Gaëlle Thomas, Nadège Gaborit, Marta Jarlier, Nelly Pirot, Martine Pugnière, Nadia Vie, Céline Gongora, Pierre Martineau, Bruno Robert, André Pèlegrin, Thierry Chardès, Christel Larbouret
Neuregulin 1 (NRG1), a ligand for HER3 and HER4 receptors, is secreted by both pancreatic tumor cells (PC) and cancer-associated fibroblasts (CAFs), the latter representing the most abundant compound of pancreatic stroma. This desmoplastic stroma contributes to Pancreatic Ductal Adenocarcinoma (PDAC) aggressiveness and therapeutic failure by promoting tumor progression, invasion and resistance to chemotherapies. In the present work, we aimed at disrupting the complex crosstalk between PC and CAF in order to prevent tumor cell proliferation...
June 20, 2018: Cancer Letters
Xu Qian, Xiaobo Nie, Wenhao Yao, Konrad Klinghammer, Holger Sudhoff, Andreas M Kaufmann, Andreas E Albers
One of the greatest challenges in systemic treatment of head and neck squamous cell carcinoma (HNSCC) is a small tumor cell population, namely, cancer stem-like cells (CSC). CSC can regenerate and maintain a heterogenic tumor by their self-renewal capacity. Their potential ability to be more resistant to and survival after chemo- and radiation therapy was also identified. Further studies have shown that reactive oxygen species (ROS) contribute to this CSC-associated resistance. In this review, we focus on the current knowledge of HNSCC-CSC, with regard to ROS as a possible and novel therapeutic approach in targeting CSC...
June 20, 2018: Seminars in Cancer Biology
Yingbin Huang, Guangyu Chen, Yang Wang, Rui He, Jun Du, Xingyuan Jiao, Qiang Tai
Hepatocellular carcinoma (HCC) is a common malignant tumor usually resistant to chemotherapy. MicroRNAs play important roles in modulation of carcinogenesis and chemoresistance, which miR-16 has been reported to mediate chemoresistance in many types of cancers. However, the role of miR-16 in HCC remains unknown. The aim of this study was to investigate whether miR-16 is participated in chemoresistance in HCC and shed light on the underlying molecular mechanisms. The findings of the current study discover that miR-16 is down-regulated in HCC tissue and cell lines...
June 20, 2018: Biochemical and Biophysical Research Communications
Yuhong Lu, Yanfeng Liu, Sebastian Oeck, Peter M Glazer
The development of small-molecule tyrosine kinase inhibitors (TKIs) specific for epidermal growth factor receptors (EGFRs) with activating mutations has led to a new paradigm in the treatment of non-small cell lung cancer (NSCLC) patients. However, most patients eventually develop resistance. Hypoxia is a key micro-environmental stress in solid tumors that is associated with poor prognosis due, in part, to acquired resistance to conventional therapy. This study, documents that long-term, moderate hypoxia promotes resistance to the EGFR TKI, gefitinib, in the NSCLC cell line, HCC827, which harbors an activating EGFR mutation...
June 22, 2018: Molecular Cancer Research: MCR
Chen-Ru Wang, Ze-Feng Wang, Lu Shi, Zhong-Chang Wang, Hai-Liang Zhu
With the increasingly acquired resistance, relapse and side effects of known marketed BRAFV600E inhibitors, it's significant to design the more effective and novel drugs. In this study, a series of novel pyrazole derivatives containing acetamide bond had been designed and synthesized on the basis of analysis of the endogenous ligands extracted from the known B-Raf co-crystals in the PDB database. Then, the compounds were evaluated for biological activities as potential BRAFV600E inhibitors. The bioassay results in vitro against three human tumor cell lines revealed that some of the compounds showed very impressed antiproliferative property...
June 15, 2018: Bioorganic & Medicinal Chemistry Letters
Sameer A Greenall, Jacqueline Donoghue, Terrance G Johns, Timothy E Adams
Hepatocellular carcinoma (HCC) is highly refractory to current therapeutics used in the clinic. DX-2647, a recombinant human antibody, potently neutralizes the action of insulin-like growth factor-II (IGF-II), a ligand for three cell-surface receptors (IGF-IR, insulin receptor A and B isoforms, and the cation-independent mannose-6-phosphate receptor) which is overexpressed in primary human HCC. DX-2647 impaired the growth of tumor xenografts of the HCC cell line, Hep3B; however, xenografts of the HCC cell line, HepG2, were largely unresponsive to DX-2647 treatment...
June 18, 2018: Translational Oncology
Maria Ferraiuolo, Claudio Pulito, Megan Finch-Edmondson, Etleva Korita, Anna Maidecchi, Sara Donzelli, Paola Muti, Massimo Serra, Marius Sudol, Sabrina Strano, Giovanni Blandino
Osteosarcoma (OS) is the most aggressive type of primary solid tumor that develops in bone. Whilst conventional chemotherapy can improve survival rates, the outcome for patients with metastatic or recurrent OS remains poor, so novel treatment agents and strategies are required. Research into new anticancer therapies has paved the way for the utilisation of natural compounds as they are typically less expensive and less toxic compared to conventional chemotherapeutics. Previously published works indicate that Agave exhibits anticancer properties, however potential molecular mechanisms remain poorly understood...
June 19, 2018: Cancer Letters
Joe Pelt, Sara Busatto, Mauro Ferrari, E Aubrey Thompson, Kabir Mody, Joy Wolfram
Clinically approved cancer therapies include small molecules, antibodies, and nanoparticles. There has been major progress in the treatment of several cancer types over recent decades. However, many challenges remain for optimal use of conventional and nanoparticle-based therapies in oncology including poor drug delivery, rapid clearance, and drug resistance. The antimalarial agent chloroquine has been found to mitigate some of these challenges by modulating cancer cells and the tissue microenvironment. Particularly, chloroquine was recently found to reduce immunological clearance of nanoparticles by resident macrophages in the liver, leading to increased tumor accumulation of nanodrugs...
June 19, 2018: Pharmacology & Therapeutics
Tasuku Kiyuna, Yasunori Tome, Takashi Murakami, Ming Zhao, Kentaro Miyake, Kentaro Igarashi, Kei Kawaguchi, Masuyo Miyake, Hiromichi Oshiro, Takashi Higuchi, Yunfeng Li, Sarah M Dry, Scott D Nelson, Tara A Russell, Mark A Eckardt, Arun S Singh, Fuminori Kanaya, Fritz C Eilber, Robert M Hoffman
Pleomorphic liposarcoma (PLPS) is a recalcitrant soft-tissue sarcoma (STS) subtype in need of transformative therapy. We have previously established a patient-derived orthotopic xenograft (PDOX) model, of PLPS with PDGFRA amplification, using surgical orthotopic implantation. In the current study, the PLPS PDOX model was randomized into 3 groups of 7 mice each: untreated control; doxorubicin (DOX)-treated; and treated with Salmonella typhimurium A1-R (S. typhimurium A1-R) expressing green fluorescent protein (GFP)...
June 22, 2018: Journal of Cellular Biochemistry
Luming Xu, Jia Liu, Jiangbo Xi, Qilin Li, Bingcheng Chang, Xianming Duan, Guobin Wang, Shuai Wang, Zheng Wang, Lin Wang
Despite the therapeutic usefulness of near-infrared irradiation (NIR)-induced potent photothermal effects (PTE) and photodynamic effects (PDE), they inevitably damage normal tissues, often posing threat to life when treating tumors adjacent to key organs or major blood vessels. In this study, the frequently overlooked, "weak" PTE and PDE (no killing capability) are employed to synergize chemotherapy against multidrug resistance (MDR) without impairing normal tissues. An NIR-responsive nanosystem, gold (Au)-nanodot-decorated hollow carbon nanospheres coated with hyaluronic acid, is synthesized as a doxorubicin (DOX) carrier with excellent photothermal and photodynamic properties...
June 21, 2018: Small
Donatella Treppiedi, Marie-Lise Jobin, Erika Peverelli, Elena Giardino, Titiwat Sungkaworn, Ulrike Zabel, Maura Arosio, Anna Spada, Giovanna Mantovani, Davide Calebiro
The cytoskeletal protein filamin A (FLNA) has been suggested to play an important role in the responsiveness of GH-secreting pituitary tumors to somatostatin receptor subtype 2 (SSTR2) agonists, by regulating SSTR2 expression and signaling. However, the underlying mechanisms are unknown. Here, we use fast multi-color single-molecule microscopy to image individual SSTR2 and FLNA molecules at the surface of living cells with unprecedented spatiotemporal resolution. We find that SSTR2 and FLNA undergo transient interactions, which occur preferentially along actin fibers and contribute to restraining SSTR2 diffusion...
June 19, 2018: Endocrinology
Balkees Abderrahman, V Craig Jordan
The signing of the National Cancer Act in 1971, was designed to take laboratory discoveries rapidly from the bench to the bedside. A "war on cancer" had been declared. Combination cytotoxic chemotherapy was predicted to cure all cancers based on the stunning success in treating childhood leukemia. Breast cancer treatments were primitive; radical mastectomy and radiation was standard of care for disease that had not spread. Ablative endocrine surgery (oophorectomy, hypophysectomy, and adrenalectomy) was a palliative last option for metastatic breast cancer...
June 19, 2018: Endocrinology
Yoshinobu Ichimura, Masaaki Komatsu
Autophagy and the Keap1-Nrf2 system are major cellular defense mechanisms against metabolic and oxidative stress. These two systems are linked via phosphorylation of the ubiquitin binding autophagy receptor protein p62/SQSTM1 in the p62-Keap1-Nrf2 pathway. The p62-Keap1-Nrf2 pathway plays a protective role in normal cells; however, recent studies indicate that this pathway induces tumorigenesis of pre-malignant cells, and promotes the growth and drug resistance of tumor cells via metabolic reprogramming mediated by Nrf2 activation...
2018: Frontiers in Oncology
Shinji Nakamichi, Masahiro Seike, Akihiko Miyanaga, Mika Chiba, Fenfei Zou, Akiko Takahashi, Arimi Ishikawa, Shinobu Kunugi, Rintaro Noro, Kaoru Kubota, Akihiko Gemma
Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non-small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs remains an inevitable problem. In this study, we aimed to discover novel therapeutic targets to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib)-resistant H2228 NSCLC cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial-mesenchymal transition (EMT), and had cancer stem cell-like (CSC) properties, suggesting drug-tolerant cancer cell subpopulations...
June 5, 2018: Oncotarget
Matias Eliseo Melendez, Renato José Silva-Oliveira, Anna Luiza Silva Almeida Vicente, Lidia Maria Rebolho Batista Arantes, Ana Carolina de Carvalho, Alberto Luis Epstein, Rui Manuel Reis, André Lopes Carvalho
Apoptosis induction has emerged as a treatment option for anticancer therapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a type II transmembrane protein, is a potent and specific pro-apoptotic protein ligand, which activates the extrinsic apoptosis pathway of the cell death receptors. Here we describe the construction and characterization of a new soluble TRAIL, sfTRAIL, stabilized with the trimerization Foldon domain from the Fibritin protein of the bacteriophage T4. Supernatants of 0...
June 5, 2018: Oncotarget
Augustin Le Naour, Renaud Mevel, Benoit Thibault, Elise Courtais, Elodie Chantalat, Jean Pierre Delord, Bettina Couderc, Julie Guillermet-Guibert, Alejandra Martinez
Background: Ovarian cancer is associated with poor prognostic outcome due to late diagnosis and to intrinsic and acquired resistance to platinum-based chemotherapy in a large number of patients. This chemoresistance is acquired through the peritoneal and ascites microenvironment by several released factors, such as IL-6,. Preclinical studies have implicated the activation of PI3K pathway in chemoresistance, showing it to extend tumor cell survival and modulate multidrug resistance. We aimed to evaluate the implication of the p110 alpha PI3K subunit in ovarian cancer chemoresistance acquisition, and to evaluate whether the STAT3 pathway can mediate resistance to PI3K inhibitors through secretion of IL6...
June 5, 2018: Oncotarget
Wanyin Chen, Leonel Nguekeu Zebaze, Jihu Dong, Laëtitia Chézeau, Perrine Inquimbert, Sylvain Hugel, Songlin Niu, Fréderic Bihel, Emmanuel Boutant, Eléonore Réal, Pascal Villa, Marie-Pierre Junier, Hervé Chneiweiss, Marcel Hibert, Jacques Haiech, Marie-Claude Kilhoffer, Maria Zeniou
Glioblastoma is a highly heterogeneous brain tumor. The presence of cancer cells with stem-like and tumor initiation/propagation properties contributes to poor prognosis. Glioblastoma cancer stem-like cells (GSC) reside in hypoxic and acidic niches favoring cell quiescence and drug resistance. A high throughput screening recently identified the laxative Bisacodyl as a cytotoxic compound targeting quiescent GSC placed in acidic microenvironments. Bisacodyl activity requires its hydrolysis into DDPM, its pharmacologically active derivative...
June 5, 2018: Oncotarget
Paola Bettinsoli, Giulia Ferrari-Toninelli, Sara Anna Bonini, Michela Guarienti, Davide Cangelosi, Luigi Varesio, Maurizio Memo
Neuroblastoma is a pediatric tumor of the sympatoadrenal lineage of the neural crest characterized by high molecular and clinical heterogeneity, which are the main causes of the poor response to standard multimodal therapy. The identification of new and selective biomarkers is important to improve our knowledge on the mechanisms of neuroblastoma progression and to find the targets for innovative cancer therapies. This study identifies a positive correlation among tropomodulins (TMODs) proteins expression and neuroblastoma progression...
June 5, 2018: Oncotarget
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