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Xu Zhu, Xiaomeng Shen, Jun Qu, Robert M Straubinger, William J Jusko
Pancreatic cancer is characterized by mutated signaling pathways and a high incidence of drug resistance. Comprehensive, large-scale proteomic analysis can provide a system-wide view of signaling networks, assist in understanding drug mechanisms of action and interactions, and serve as a useful tool for pancreatic cancer research. In this study, liquid chromatography-mass spectrometry-based proteomic analysis was applied to characterize the combination of gemcitabine and birinapant in pancreatic cancer cells, which was shown previously to be synergistic...
2018: Frontiers in Pharmacology
Nyree Crawford, Manuela Salvucci, Christian T Hellwig, Frank A Lincoln, Ruth E Mooney, Carla L O'Connor, Jochen Hm Prehn, Daniel B Longley, Markus Rehm
Apoptosis resistance contributes to treatment failure in colorectal cancer (CRC). New treatments that reinstate apoptosis competency have potential to improve patient outcome but require predictive biomarkers to target them to responsive patient populations. Inhibitor of apoptosis proteins (IAPs) suppress apoptosis, contributing to drug resistance; IAP antagonists such as TL32711 have therefore been developed. We developed a systems biology approach for predicting response of CRC cells to chemotherapy and TL32711 combinations in vitro and in vivo...
March 2, 2018: Cell Death and Differentiation
Roman C Brands, Mario J J Scheurer, Stefan Hartmann, Axel Seher, Alexander C Kübler, Urs D A Müller-Richter
Inhibitor of apoptosis proteins, which are overexpressed in head and neck squamous cell carcinoma (HNSCC), may cause therapeutic resistance. Using SMAC mimetic compounds, including birinapant, to degrade and/or inhibit these proteins and sensitize apoptosis may enhance therapies in HNSCC. Fas expression was analyzed in nine HNSCC cell lines and one keratinocyte cell line via flow cytometry. These cell lines were treated with Fas ligand-Fc (FasL) and birinapant, a bivalent SMAC mimetic, in mono and combination therapies...
March 2018: Oncology Letters
Levent Dizdar, Lisa M Jünemann, Thomas A Werner, Pablo E Verde, Stephan E Baldus, Nikolas H Stoecklein, Wolfram T Knoefel, Andreas Krieg
Based on their overexpression and important roles in progression and therapy-resistance in malignant diseases, the inhibitor of apoptosis protein family (IAP) members, survivin and X-linked inhibitor of apoptosis protein (XIAP), represent attractive candidates for targeted therapy. The present study investigated the prognostic and biological relevance of survivin and XIAP in esophageal squamous-cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Survivin and XIAP expression was analyzed by immunohistochemistry using tissue microarrays containing 120 ESCC and 90 EAC samples as well as the corresponding non-neoplastic esophageal mucosa samples...
March 2018: Oncology Letters
Xue Wang, Jin Niu, Jun Li, Xiaomeng Shen, Shichen Shen, Robert M Straubinger, Jun Qu
Despite decades of effort, pancreatic adenocarcinoma (PDAC) remains an intractable clinical challenge. An insufficient understanding of mechanisms underlying tumor cell responses to chemotherapy contributes significantly to the lack of effective treatment regimens. Here, paclitaxel, a first-line chemotherapeutic agent, was observed to interact synergistically with birinapant, a Second Mitochondrial-derived Activator of Caspases mimetic. Therefore, we investigated molecular-level drug interaction mechanisms using comprehensive, reproducible, and well-controlled ion-current-based MS1 quantification (IonStar)...
January 22, 2018: Molecular & Cellular Proteomics: MCP
Thomas Artur Werner, Inga Nolten, Levent Dizdar, Jasmin Riemer, Sina Christin Schütte, Pablo Emilio Verde, Katharina Raba, Matthias Schott, Wolfram Trudo Knoefel, Andreas Krieg
Follicular thyroid cancer's (FTC) excellent long-term prognosis is mainly dependent on complete surgical removal and postoperative radioactive iodine (RAI) treatment. However, once the tumour becomes RAI refractory the 10-year disease specific survival rate drops below 10 %. The aim of our study was to evaluate the prognostic and biological role of the TRAIL system in FTC and to elucidate the influence of small molecule mediated antagonization of inhibitor of apoptosis proteins (IAPs) on TRAIL-sensitivity in vitro...
January 9, 2018: Endocrine-related Cancer
Michael John Cekay, Stefanie Roesler, Tanja Frank, Anne-Kathrin Knuth, Ines Eckhardt, Simone Fulda
Since cancer cells often evade apoptosis, induction of necroptosis as another mode of programmed cell death is considered a promising therapeutic alternative. Here, we identify a novel synergistic interaction of Smac mimetics that antagonize x-linked Inhibitor of Apoptosis (XIAP), cellular Inhibitor of Apoptosis (cIAP) 1 and 2 with interferon (IFN)γ to induce necroptosis in apoptosis-resistant cancer cells in which caspase activation is blocked. This synergism is confirmed by calculation of combination indices (CIs) and found in both solid and hematological cancer cell lines as well as for different Smac mimetics (i...
December 1, 2017: Cancer Letters
V La, R Fujikawa, D M Janzen, M Nunez, L Bainvoll, L Hwang, K Faull, G Lawson, S Memarzadeh
Platinum drugs are the frontline therapy in many carcinomas, including high-grade serous ovarian cancers. Clinically, high-grade serous carcinomas have an apparent complete response to carboplatin, but tumors invariably recur and response to platinum drugs diminishes over time. Standard of care prohibits re-administration of platinum drugs to these patients who are labeled as having platinum-resistant disease. In this stage patients are treated with non-platinum agents and outcomes are often poor. In vivo and in vitro data presented here demonstrate that this clinical dogma should be challenged...
2017: NPJ Precision Oncology
Conor J Kearney, Najoua Lalaoui, Andrew J Freeman, Kelly M Ramsbottom, John Silke, Jane Oliaro
Smac-mimetics are emerging as promising anti-cancer agents and are being evaluated in clinical trials for a variety of malignancies. Smac-mimetics can induce TNF production from a subset of tumor cells and simultaneously sensitize them to TNF-induced apoptosis. However, TNF derived from other cellular sources, such as cytotoxic lymphocytes (CLs) within the tumor, may also contribute to the anti-tumor activity of SMs. Here, we show that CD8+ T cells and NK cells potently kill tumor cells in the presence of the SM, birinapant...
October 2017: Cell Death and Differentiation
Li Zhao, Guoshan Yang, Hao Bai, Minghui Zhang, Dongcheng Mou
Second mitochondria-derived activator of caspases (SMAC) mimetics is a class of new anticancer agents. However, most cancers exhibit de novo or acquired resistance to SMAC mimetics, posting a problem for broad applications in clinic, and highlighting the necessity of exploring combinational strategies to circumvent SMAC mimetic-resistance. We here showed that Norcantharidin, a drug that is currently being used in cancer treatment, significantly enhanced SMAC mimetic Birinapant-mediated cell viability inhibition and robustly promoted apoptosis in established breast carcinoma cell lines, as well as in primary breast carcinoma cells...
April 18, 2017: Oncotarget
Vesna Vetma, Jan Rožanc, Emilie M Charles, Christian T Hellwig, Leonidas G Alexopoulos, Markus Rehm
Antagonists of inhibitor of apoptosis proteins (IAPs), alone or in combination with genotoxic therapeutics, have been shown to efficiently induce cell death in various solid tumours. The IAP antagonist birinapant is currently being tested in phase II clinical trials. We herein aimed to investigate the in vitro anti-tumour efficacy of dacarbazine, both as a single agent and in combination with birinapant, in melanoma cell lines. Covering clinically relevant drug concentration ranges, we conducted a total of 5400 measurements in a panel of 12 human melanoma cell lines representing different stages of disease progression...
March 23, 2017: Oncology Research
Hongxiang Liu, Rui Liao, Kun He, Xiwen Zhu, Peizhi Li, Jianping Gong
It was demonstrated that second mitochondria-derived activator of caspases (SMAC) mimetic inhibites tumor necrosis factor receptor-associated factor 3 (TRAF3) degradation and the mitogen-activated protein kinase (MAPK) signaling pathway activation induced by lipopolysaccharide (LPS) in vitro. However, the effect of Smac mimetic in vivo is not clear. The present study was to investigate the role of Smac mimetic in LPS-induced liver injury in mice and its possible mechanism. An animal model of LPS-induced liver injury was established by intraperitoneally injecting mice with 10mg/kg LPS pretreatment with or without Smac mimetic birinapant (30mg/kg body weight)...
March 9, 2017: Immunology Letters
Effrosini G Panayotopoulou, Anna-Katharina Müller, Melanie Börries, Hauke Busch, Guohong Hu, Sima Lev
Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines...
July 11, 2017: Oncotarget
Alex Philchenkov, Koh Miura
Since the acquired resistance of cells to apoptosis is one of the major hallmarks of cancer, the endogenous inhibitors of apoptosis can be regarded as promising targets in the design of anticancer therapeutics. In addition to their antiapoptotic activity, inhibitor of apoptosis proteins (IAPs) are able to regulate numerous other cell functions, including proliferation, differentiation, and migration, as well as proinflammatory and immune responses. Study of the IAP family as target molecules in targeted therapies has recently focused on SMAC mimetics as synthetic IAP antagonists that have been under development as promising therapeutics...
2016: Critical Reviews in Oncogenesis
Philippos Perimenis, Apostolos Galaris, Alexandra Voulgari, Margarita Prassa, Alexander Pintzas
BACKGROUND: High expression levels of Inhibitors of Apoptosis Proteins (IAPs) have been correlated with poor cancer prognosis and block the cell death pathway by interfering with caspase activation. SMAC-mimetics are small-molecule inhibitors of IAPs that mimic the endogenous SMAC and promote the induction of cell death by neutralizing IAPs. METHODS: In this study, anti-tumour activity of new SMAC-mimetics Birinapant and AT-406 is evaluated against colorectal adenocarcinoma cells and IAP cross-talk with either oncogenic BRAF or BCL-2, or with the TRAIL are further exploited towards rational combined protocols...
August 12, 2016: BMC Cancer
Danielle F Eytan, Grace E Snow, Sophie Carlson, Adeeb Derakhshan, Anthony Saleh, Stephen Schiltz, Hui Cheng, Suresh Mohan, Shaleeka Cornelius, Jamie Coupar, Anastasia L Sowers, Lidia Hernandez, James B Mitchell, Christina M Annunziata, Zhong Chen, Carter Van Waes
Comparison of tumors from The Cancer Genome Atlas (TCGA) reveals that head and neck squamous cell carcinomas (HNSCC) harbor the most frequent genomic amplifications of Fas-associated death domain (FADD), with or without Baculovirus inhibitor of apoptosis repeat containing BIRC2 (cIAP1), affecting about 30% of patients in association with worse prognosis. Here, we identified HNSCC cell lines harboring FADD/BIRC2 amplifications and overexpression by exome sequencing, RT-PCR, and Western blotting. In vitro, FADD or BIRC2 siRNA knockdown inhibited HNSCC displaying amplification and increased expression of these genes, supporting their functional importance in promoting proliferation...
September 15, 2016: Cancer Research
Jennifer Richmond, Alissa Robbins, Kathryn Evans, Dominik Beck, Raushan T Kurmasheva, Catherine A Billups, Hernan Carol, Sue Heatley, Rosemary Sutton, Glenn M Marshall, Deborah White, John Pimanda, Peter J Houghton, Malcolm A Smith, Richard B Lock
Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL...
August 1, 2016: Cancer Research
Dong-Joon Min, Siping He, Jeffrey E Green
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer currently lacking targeted therapies. Our previous work demonstrated a therapeutic synergism with gemcitabine (GEM) and the CHK1 inhibitor (AZD7762) combination treatment in a TNBC cell line. We hypothesized that the response to this combination therapy would differ among heterogeneous TNBC patients and that addition of a SMAC mimetic (TL32711) could improve efficacy. MATERIALS AND METHODS: Therapeutic responses to GEM, GEM/AZD7762, and GEM/AZD7762/TL32711 combinations were investigated by XTT assays and western blotting of cell cycle and apoptosis-related proteins in ten TNBC cell lines...
June 2016: Anticancer Research
Scott McComb, Júlia Aguadé-Gorgorió, Lena Harder, Blerim Marovca, Gunnar Cario, Cornelia Eckert, Martin Schrappe, Martin Stanulla, Arend von Stackelberg, Jean-Pierre Bourquin, Beat C Bornhauser
More precise treatment strategies are urgently needed to decrease toxicity and improve outcomes for treatment-refractory leukemia. We used ex vivo drug response profiling of high-risk, relapsed, or refractory acute lymphoblastic leukemia (ALL) cases and identified a subset with exquisite sensitivity to small-molecule mimetics of the second mitochondria-derived activator of caspases (SMAC) protein. Potent ex vivo activity of the SMAC mimetic (SM) birinapant correlated with marked in vivo antileukemic effects, as indicated by delayed engraftment, decreased leukemia burden, and prolonged survival of xenografted mice...
May 18, 2016: Science Translational Medicine
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