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https://www.readbyqxmd.com/read/27846237/integrated-genomics-identifies-mir-32-mcl-1-pathway-as-a-critical-driver-of-melanomagenesis-implications-for-mir-replacement-and-combination-therapy
#1
Prasun J Mishra, Pravin J Mishra, Glenn Merlino
AIMS: Cutaneous malignant melanoma is among the deadliest human cancers, broadly resistant to most clinical therapies. A majority of patients with BRAFV600E melanomas respond well to inhibitors such as vemurafenib, but all ultimately relapse. Moreover, there are no viable treatment options available for other non-BRAF melanoma subtypes in the clinic. A key to improving treatment options lies in a better understanding of mechanisms underlying melanoma progression, which are complex and heterogeneous...
2016: PloS One
https://www.readbyqxmd.com/read/26556430/targeting-bcl2-proteins-for-the-treatment-of-solid-tumours
#2
REVIEW
Meike Vogler
Due to their central role in the regulation of apoptosis, the antiapoptotic BCL2-proteins are highly promising targets for the development of novel anticancer treatments. To this end, several strategies have been developed to inhibit BCL2, BCL-XL, BCL-w, and MCL1. While early clinical trials in haematological malignancies demonstrated exciting single-agent activity of BCL2-inhibitors, the response in solid tumours was limited, indicating that, in solid tumours, different strategies have to be developed in order to successfully treat patients with BCL2-inhibitors...
2014: Advances in Medicine
https://www.readbyqxmd.com/read/26032425/pancreatic-cancer-combination-therapy-using-a-bh3-mimetic-and-a-synthetic-tetracycline
#3
Bridget A Quinn, Rupesh Dash, Siddik Sarkar, Belal Azab, Praveen Bhoopathi, Swadesh K Das, Luni Emdad, Jun Wei, Maurizio Pellecchia, Devanand Sarkar, Paul B Fisher
Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small-molecule BH3 mimetic, inhibits the function of antiapoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity. Here, we offer evidence of the combinatorial antitumor potency of these agents in several preclinical models of pancreatic cancer. Sabutoclax induced growth arrest and apoptosis in pancreatic cancer cells and synergized with minocycline to yield a robust mitochondria-mediated caspase-dependent cytotoxicity...
June 1, 2015: Cancer Research
https://www.readbyqxmd.com/read/26009874/mcl-1-is-an-important-therapeutic-target-for-oral-squamous-cell-carcinomas
#4
Santanu Maji, Sabindra K Samal, Laxmipriya Pattanaik, Swagatika Panda, Bridget A Quinn, Swadesh K Das, Devanand Sarkar, Maurizio Pellecchia, Paul B Fisher, Rupesh Dash
Oral and oropharyngeal cancers are the sixth most common cancers worldwide. Despite intensive investigation, oral squamous cell carcinomas (OSCC) represent a clinical challenge resulting in significant morbidity and mortality. Resistance to cell death is common in OSCC and is often mediated by the Bcl-2 family proteins. Among all anti-apoptotic Bcl-2 family members, Mcl-1 functions as a major survival factor, particularly in solid cancers. Despite the confirmed importance of Mcl-1 in several neoplasms, the role of Mcl-1 in OSCC survival has yet to be explored...
June 30, 2015: Oncotarget
https://www.readbyqxmd.com/read/23633928/sabutoclax-bi97c1-and-bi112d1-putative-inhibitors-of-mcl-1-induce-mitochondrial-fragmentation-either-upstream-of-or-independent-of-apoptosis
#5
Shankar Varadarajan, Michael Butterworth, Jun Wei, Maurizio Pellecchia, David Dinsdale, Gerald M Cohen
Owing to the high levels of antiapoptotic B-cell lymphoma 2 (BCL-2) family members observed in several cancers, there has been a major effort to develop inhibitors of the BCL2-family as chemotherapeutic agents. Of the different members in the BCL-2 family, myeloid cell leukemia sequence 1 (MCL-1) is commonly amplified in human tumors and is associated with their relapse and chemoresistance. As a result, specific inhibitors of MCL-1 are being designed to treat resistant tumors. However, there is increasing evidence for other nonapoptotic roles of the BCL-2 family, ranging from ionic homeostasis and autophagy to the regulation of fission-fusion dynamics in subcellular organelles, including the endoplasmic reticulum and mitochondria...
May 2013: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/23333150/a-pan-bcl2-inhibitor-renders-bone-marrow-resident-human-leukemia-stem-cells-sensitive-to-tyrosine-kinase-inhibition
#6
Daniel J Goff, Angela Court Recart, Anil Sadarangani, Hye-Jung Chun, Christian L Barrett, Maryla Krajewska, Heather Leu, Janine Low-Marchelli, Wenxue Ma, Alice Y Shih, Jun Wei, Dayong Zhai, Ifat Geron, Minya Pu, Lei Bao, Ryan Chuang, Larisa Balaian, Jason Gotlib, Mark Minden, Giovanni Martinelli, Jessica Rusert, Kim-Hien Dao, Kamran Shazand, Peggy Wentworth, Kristen M Smith, Christina A M Jamieson, Sheldon R Morris, Karen Messer, Lawrence S B Goldstein, Thomas J Hudson, Marco Marra, Kelly A Frazer, Maurizio Pellecchia, John C Reed, Catriona H M Jamieson
Leukemia stem cells (LSCs) play a pivotal role in the resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors (TKIs) and its progression to blast crisis (BC), in part, through the alternative splicing of self-renewal and survival genes. To elucidate splice-isoform regulators of human BC LSC maintenance, we performed whole-transcriptome RNA sequencing, splice-isoform-specific quantitative RT-PCR (qRT-PCR), nanoproteomics, stromal coculture, and BC LSC xenotransplantation analyses. Cumulatively, these studies show that the alternative splicing of multiple prosurvival BCL2 family genes promotes malignant transformation of myeloid progenitors into BC LSCS that are quiescent in the marrow niche and that contribute to therapeutic resistance...
March 7, 2013: Cell Stem Cell
https://www.readbyqxmd.com/read/22931411/selected-approaches-for-rational-drug-design-and-high-throughput-screening-to-identify-anti-cancer-molecules
#7
REVIEW
Michael Hedvat, Luni Emdad, Swadesh K Das, Keetae Kim, Santanu Dasgupta, Shibu Thomas, Bin Hu, Shan Zhu, Rupesh Dash, Bridget A Quinn, Regina A Oyesanya, Timothy P Kegelman, Upneet K Sokhi, Siddik Sarkar, Eda Erdogan, Mitchell E Menezes, Praveen Bhoopathi, Xiang-Yang Wang, Martin G Pomper, Jun Wei, Bainan Wu, John L Stebbins, Paul W Diaz, John C Reed, Maurizio Pellecchia, Devanand Sarkar, Paul B Fisher
Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specificpromoter derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI-97C1) displays potent anti-tumor activity against a diverse spectrum of human tumors...
November 2012: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/22904682/sabutoclax-a-mcl-1-antagonist-inhibits-tumorigenesis-in-transgenic-mouse-and-human-xenograft-models-of-prostate-cancer
#8
Roger S Jackson, William Placzek, Ana Fernandez, Shabnam Ziaee, Chia-Yi Chu, Jun Wei, John Stebbins, Shinichi Kitada, Gloria Fritz, John C Reed, Leland W Chung, Maurizio Pellecchia, Neil A Bhowmick
Resistance to available therapeutic agents has been a common problem thwarting progress in treatment of castrate-resistant and metastatic prostate cancer (PCa). Overexpression of the Bcl-2 family members, including Mcl-1, in PCa cells is known to inhibit intracellular mitochondrial-dependent apoptosis. Here we report the development of a novel transgenic mouse model that spontaneously develops prostatic intraepithelial neoplasia and adenocarcinoma by the inducible, conditional knockout of transforming growth factor β receptor type II in stromal fibroblastic cells (Tgfbr2(ColTKO))...
July 2012: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/21953453/identification-of-a-novel-mcl-1-protein-binding-motif
#9
William J Placzek, Mattia Sturlese, Bainan Wu, Jason F Cellitti, Jun Wei, Maurizio Pellecchia
Recent characterization of Mcl-1 as the primary anti-apoptotic Bcl-2 family member expressed in solid tumors, coupled with its ability to enable therapeutic resistance, has provided the impetus for further study into how Mcl-1 is involved in apoptosis signaling. Here, we employ Sabutoclax, a potent and effective Mcl-1 antagonist, as a competing agent to screen a randomized 12-residue phage display library for peptides that bind strongly to the Bcl-2 homology 3 (BH3) binding groove of Mcl-1. Although the screen identified a number of α-helical peptides with canonical BH3 domain sequences, it also isolated a pair of unique peptide sequences...
November 18, 2011: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/21780116/enhanced-delivery-of-mda-7-il-24-using-a-serotype-chimeric-adenovirus-ad-5-3-in-combination-with-the-apogossypol-derivative-bi-97c1-sabutoclax-improves-therapeutic-efficacy-in-low-car-colorectal-cancer-cells
#10
Belal Azab, Rupesh Dash, Swadesh K Das, Sujit K Bhutia, Xue-Ning Shen, Bridget A Quinn, Siddik Sarkar, Xiang-Yang Wang, Michael Hedvat, Igor P Dmitriev, David T Curiel, Steven Grant, Paul Dent, John C Reed, Maurizio Pellecchia, Devanand Sarkar, Paul B Fisher
Adenovirus (Ad)-based gene therapy represents a potentially viable strategy for treating colorectal cancer. The infectivity of serotype 5 adenovirus (Ad.5), routinely used as a transgene delivery vector, is dependent on Coxsackie-adenovirus receptors (CAR). CAR expression is downregulated in many cancers thus preventing optimum therapeutic efficiency of Ad.5-based therapies. To overcome the low CAR problem, a serotype chimerism approach was used to generate a recombinant Ad (Ad.5/3) that is capable of infecting cancer cells via Ad...
May 2012: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/21555592/apogossypol-derivative-bi-97c1-sabutoclax-targeting-mcl-1-sensitizes-prostate-cancer-cells-to-mda-7-il-24-mediated-toxicity
#11
Rupesh Dash, Belal Azab, Bridget A Quinn, Xuening Shen, Xiang-Yang Wang, Swadesh K Das, Mohamed Rahmani, Jun Wei, Michael Hedvat, Paul Dent, Igor P Dmitriev, David T Curiel, Steven Grant, Bainan Wu, John L Stebbins, Maurizio Pellecchia, John C Reed, Devanand Sarkar, Paul B Fisher
Limited options are available for treating patients with advanced prostate cancer (PC). Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), an IL-10 family cytokine, exhibits pleiotropic anticancer activities without adversely affecting normal cells. We previously demonstrated that suppression of the prosurvival Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1), is required for mda-7/IL-24-mediated apoptosis of prostate carcinomas. Here we demonstrate that pharmacological inhibition of Mcl-1 expression with the unique Apogossypol derivative BI-97C1, also called Sabutoclax, is sufficient to sensitize prostate tumors to mda-7/IL-24-induced apoptosis, whereas ABT-737, which lacks efficacy in inhibiting Mcl-1, does not sensitize mda-7/IL-24-mediated cytotoxicity...
May 24, 2011: Proceedings of the National Academy of Sciences of the United States of America
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