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Molecular analysis of chemotherapy resistance

Ayse Ayhan, Elisabetta Kuhn, Ren-Chin Wu, Hiroshi Ogawa, Asli Bahadirli-Talbott, Tsui-Lien Mao, Haruhiko Sugimura, Ie-Ming Shih, Tian-Li Wang
Ovarian clear cell carcinoma is a unique type of ovarian cancer, often derived from endometriosis, and advanced-stage disease has a dismal prognosis primarily due to the resistance to conventional chemotherapy. Previous studies have shown frequent somatic mutations in ARID1A, PIK3CA, hTERT promoter, and amplification of ZNF217; however, the molecular alterations that are associated with its aggressiveness remain largely unknown. This study examined and compared cyclin E1 expression in endometriosis-related ovarian tumors, with the aim of determining the relationship between hTERT mutations and ARID1A expression and evaluating the effects of these molecular alterations on patient survival...
October 21, 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Raimonda Kubiliūtė, Indrė Šulskytė, Kristina Daniūnaitė, Rimantas Daugelavičius, Sonata Jarmalaitė
BACKGROUND AND AIM: Resistance to chemotherapy is the key obstacle to the effective treatment of various cancers. Accumulating evidence suggests significant involvement of the epithelial-to-mesenchymal transition (EMT) in the chemoresistance of most cancer types. This study aimed at analyzing the gene expression profile of doxorubicin (DOX)-resistant colorectal cancer cells CX-1. MATERIALS AND METHODS: DOX-resistant CX-1 cell sublines were acquired by stepwise increment of DOX concentrations in cell growth media...
September 29, 2016: Medicina
Lucy Ireland, Almudena Santos, Muhammad S Ahmed, Carolyn Rainer, Sebastian R Nielsen, Valeria Quaranta, Ulrike Weyer-Czernilofsky, Danielle D Engle, Pedro Perez-Mancera, Sarah E Coupland, Azzam F Taktak, Thomas Bogenrieder, David A Tuveson, Fiona Campbell, Michael C Schmid, Ainhoa Mielgo
Tumor associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors 1 and 2 (IGF), which activate Insulin/IGF receptors on pancreatic cancer cells...
October 14, 2016: Cancer Research
Yawei Wang, Haiyan Zhang, Jisheng Li, Xiuwen Wang
An acquired T798M gatekeeper mutation in human epidermal growth factor receptor 2 (HER2) kinase can cause drug resistance to anti-HER2 chemotherapy drugs in lung cancer. Previously, the reversible pan-kinase inhibitor Staurosporine has been found to selectively inhibit the HER2 T798M mutant over wild-type kinase, suggesting that the Staurosporine scaffold is potentially to develop mutant-selective inhibitors. Here, we systematically evaluated the chemical space of Staurosporine scaffold-based compounds in response to HER2 T798M mutation at structural, energetic and molecular levels by using an integrated analysis strategy...
October 1, 2016: Chemistry & Biodiversity
Lanfang Li, Qingya Luo, Zhe Xie, Guiqin Li, Chengyi Mao, Yi Liu, Xin Wen, Na Yin, Jianzhong Cao, Jing Wang, Li Li, Jianhua Yu, Fang Wang, Ping Yi
BACKGROUND: Ovarian cancer is the most lethal type of malignant tumor in gynecological cancers and is associated with a high percentage of late diagnosis and chemotherapy resistance. Thus, it is urgent to identify a tumor marker or a molecular target that allows early detection and effective treatment. RNA-binding proteins (RBPs) are crucial in various cellular processes at the post-transcriptional level. The eukaryotic translation initiation factor 4 gamma, 1(eIF4G1), an RNA-binding protein, facilitates the recruitment of mRNA to the ribosome, which is a rate-limiting step during the initiation phase of protein synthesis...
2016: PloS One
Waleed M Sweileh, Naser Y Shraim, Samah W Al-Jabi, Ansam F Sawalha, Adham S AbuTaha, Sa'ed H Zyoud
BACKGROUND: Antimicrobial resistance is a global public health challenge and carbapenem resistance, in particular, is considered an urgent global health threat. This study was carried out to give a bibliometric overview of literature on carbapenem resistance. In specific, number of publications, top productive countries and institutes, highly cited articles, citation analysis, co-authorships, international collaboration, top active authors, and journals publishing articles on carbapenem resistance were analyzed and discussed...
2016: Annals of Clinical Microbiology and Antimicrobials
TianJun Chen, Hui Ren, Asmitanand Thakur, Tian Yang, Yang Li, Shuo Zhang, Ting Wang, MingWei Chen
Klotho is originally discovered as an anti-aging gene and recently identified as a tumor suppressor in various human cancers. Drug resistance is a major obstacle to affect the treatment of chemotherapy. In the present study, we explore the role of klotho on drug resistance in human lung cancers and investigate the mechanism of klotho on drug resistance in lung cancer cells. First, we detected a panel of six human lung cancer cell lines, including H460, SK-MES-1, cisplatin (DDP)-resistant A549/DDP, its parental subline A549, docetaxel (DTX)-resistant SPC-A-1/DTX, and SPC-A-1 by western blotting analysis...
September 23, 2016: DNA and Cell Biology
Anja Lisa Riediger, Steffen Dietz, Uwe Schirmer, Michael Meister, Ingrid Heinzmann-Groth, Marc Schneider, Thomas Muley, Michael Thomas, Holger Sültmann
Long-lasting success in lung cancer therapy using tyrosine kinase inhibitors (TKIs) is rare since the tumors develop resistance due to the occurrence of molecularly altered subclones. The aim of this study was to monitor tumors over time based on the quantity of mutant plasma DNA and to identify early indications for therapy response and tumor progression. Serial plasma samples from lung adenocarcinoma patients treated with TKIs were used to quantify EGFR and KRAS mutations in circulating DNA by digital PCR...
2016: Scientific Reports
Sebo Kim, Varsha Sundaresan, Lei Zhou, Tamer Kahveci
One of fundamental challenges in cancer studies is that varying molecular characteristics of different tumor types may lead to resistance to certain drugs. As a result, the same drug can lead to significantly different results in different types of cancer thus emphasizing the need for individualized medicine. Individual prediction of drug response has great potential to aid in improving the clinical outcome and reduce the financial costs associated with prescribing chemotherapy drugs to which the patient's tumor might be resistant...
2016: PloS One
Stephanie L Ham, Ramila Joshi, Gary D Luker, Hossein Tavana
Solid tumors develop as 3D tissue constructs. As tumors grow larger, spatial gradients of nutrients and oxygen and inadequate diffusive supply to cells distant from vasculature develops. Hypoxia initiates signaling and transcriptional alterations to promote survival of cancer cells and generation of cancer stem cells (CSCs) that have self-renewal and tumor-initiation capabilities. Both hypoxia and CSCs are associated with resistance to therapies and tumor relapse. This study demonstrates that 3D cancer cell models, known as tumor spheroids, generated with a polymeric aqueous two-phase system (ATPS) technology capture these important biological processes...
September 7, 2016: Advanced Healthcare Materials
Talha Shafi, Ishrat Jabeen
ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP/ABCG2) are major determinant of pharmacokinetic, safety and efficacy profiles of drugs thereby effluxing a broad range of endogenous substances across the plasma membrane. Overexpression of these transporters in various tumors is also implicated in the development of multidrug resistance (MDR) and thus, hampers the success of cancer chemotherapy. Modulators of these efflux transporters in combination with chemotherapeutics could be a promising concept to increase the effective intracellular concentration of anticancer drugs...
August 31, 2016: Current Cancer Drug Targets
Solomon L Woldu, James F Amatruda, Aditya Bagrodia
PURPOSE OF REVIEW: Testicular germ cell tumors (TGCTs) are a model for curable cancer because of exquisite chemosensitivity and incorporation of multimodal therapy. Nevertheless, our ability to predict metastases in early-stage disease and responders to chemotherapy in advanced disease is limited. Treatment options for cisplatin-resistant disease are sparse. A further understanding of TGCT biology may allow for more precise patient counseling and identify novel therapies in patients with cisplatin-resistant disease...
August 31, 2016: Current Opinion in Urology
Duane H Hamilton, Mario Roselli, Patrizia Ferroni, Leopoldo Costarelli, Francesco Cavaliere, Mariateresa Taffuri, Claudia Palena, Fiorella Guadagni
Patients diagnosed with triple-negative breast cancer (TNBC) have a high rate of tumor metastasis and a poor prognosis. The treatment option for these patients is currently chemotherapy, which results in very low response rates. Strategies that exploit the immune system for the treatment of cancer have now shown the ability to improve survival in several tumor types. Identifying potential targets for immune therapeutic interventions is an important step in developing novel treatments for TNBC. In this study, in silico analysis of publicly available datasets and immunohistochemical analysis of primary and metastatic tumor biopsies from TNBC patients were conducted to evaluate the expression of the transcription factor brachyury, which is a driver of tumor metastasis and resistance and a target for cancer vaccine approaches...
October 2016: Endocrine-related Cancer
Yukiko Masaki, Yoichi Shimizu, Takeshi Yoshioka, Fei Feng, Songji Zhao, Kenichi Higashino, Yoshito Numata, Yuji Kuge
Hypoxia, or low oxygen concentration, is a key factor promoting tumor progression and angiogenesis and resistance of cancer to radiotherapy and chemotherapy. 2-Nitroimidazole-based agents have been widely used in pathological and nuclear medicine examinations to detect hypoxic regions in tumors; in particular, pimonidazole is used for histochemical staining of hypoxic regions. It is considered to accumulate in hypoxic cells via covalent binding with macromolecules or by forming reductive metabolites after reduction of its nitro group...
2016: PloS One
Satoshi Matsukuma, Kiyoshi Yoshimura, Tomio Ueno, Atsunori Oga, Moeko Inoue, Yusaku Watanabe, Atsuo Kuramasu, Masanori Fuse, Ryoichi Tsunedomi, Satoshi Nagaoka, Hidetoshi Eguchi, Hiroto Matsui, Yoshitaro Shindo, Noriko Maeda, Yoshihiro Tokuhisa, Reo Kawano, Tomoko Furuya-Kondo, Hiroshi Itoh, Shigefumi Yoshino, Shoichi Hazama, Masaaki Oka, Hiroaki Nagano
Cancer stem-like cells (CSLCs) in solid tumors are thought to be resistant to conventional chemotherapy or molecular targeting therapy and to contribute to cancer recurrence and metastasis. In this study, we aimed to identify a biomarker of pancreatic CSLCs (P-CSLCs). P-CSLC-enriched population was generated from pancreatic cancer cell lines using our previously reported method and its protein expression profile was compared with that of parental cells by two-dimensional electrophoresis and tandem mass spectrometry...
August 25, 2016: Cancer Science
Kyogo Suzuki, Yusuke Okuno, Nozomu Kawashima, Hideki Muramatsu, Tatsuya Okuno, Xinan Wang, Shinsuke Kataoka, Yuko Sekiya, Motoharu Hamada, Norihiro Murakami, Daiei Kojima, Kotaro Narita, Atsushi Narita, Hirotoshi Sakaguchi, Kimiyoshi Sakaguchi, Nao Yoshida, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, Kazuko Kudo, Koji Kato, Seiji Kojima
PURPOSE: Acute lymphoblastic leukemia (ALL) makes up a significant proportion of all pediatric cancers, and relapsed ALL is a leading cause of cancer-associated deaths in children. Identification of risk factors and druggable molecular targets in ALL can lead to a better stratification of treatments and subsequent improvement in prognosis. PATIENTS AND METHODS: We enrolled 59 children with relapsed or primary refractory ALL who were treated in our institutions. We primarily performed RNA sequencing (RNA-seq) using patients' leukemic cells to comprehensively detect gene fusions and analyze gene expression profiles...
October 1, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Adrian P Wiegmans, Mariska Miranda, Shu Wen Wen, Fares Al-Ejeh, Andreas Möller
The molecular rationale to induce synthetic lethality, by targeting defective homologous recombination repair in triple negative breast cancer (TNBC), has proven to have several shortcomings. Not meeting the expected minimal outcomes in clinical trials has highlighted common clinical resistance mechanisms including; increased expression of the target gene PARP1, increased expression or reversion mutation of BRCA1, or up-regulation of the compensatory homologous recombination protein RAD51. Indeed, RAD51 has been demonstrated to be an alternative synthetic lethal target in BRCA1-mutated cancers...
August 5, 2016: Oncotarget
Birgit C Weyhenmeyer, Janis Noonan, Maximilian L Würstle, Frank A Lincoln, Grainne Johnston, Markus Rehm, Brona M Murphy
Genotoxic chemotherapy with temozolomide (TMZ) is a mainstay of treatment for glioblastoma (GBM); however, at best, TMZ provides only modest survival benefit to a subset of patients. Recent insight into the heterogeneous nature of GBM suggests a more personalized approach to treatment may be necessary to overcome cancer drug resistance and improve patient care. These include novel therapies that can be used both alone and with TMZ to selectively reactivate apoptosis within malignant cells. For this approach to work, reliable molecular signatures that can accurately predict treatment responsiveness need to be identified first...
August 1, 2016: Oncotarget
Xin Ren, Hao Liu, Mingjie Zhang, Mengjun Wang, Shiyin Ma
Hypopharyngeal cancer is a distinct type of malignant head and neck tumor, which exhibits low sensitivity to anti-cancer drugs. The importance of developing methods for reducing chemotherapy resistance, and improving and enhancing prognosis has previously been emphasized and is considered a challenge for effective clinical treatment of hypopharyngeal cancer. The current study investigated the effects of co‑expression of inhibitor of growth protein 4 (ING4) and P53, a tumor suppressor gene, on chemosensitivity to cisplatin in human hypopharyngeal cancer xenografts in vivo, and the potential molecular mechanisms involved...
September 2016: Molecular Medicine Reports
Qin Yu, Zhao-Yu Liu, Qiong Chen, Ju-Sheng Lin
Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality in part due to its high resistance to chemotherapeutic drugs. The anti-apoptotic Mcl-1 expression has been reported as a resistance factor in various types of tumors. Here, we investigated the expression of Mcl-1 in hepatoma cells and HCC tissues and its relationship with p53, and analyzed the possibility of the gene as a molecular target for HCC therapy. HCC specimens of 30 patients were examined by immunohistochemistry for Mcl-1 and p53 expression...
August 2016: Journal of Huazhong University of Science and Technology. Medical Sciences
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