sabutoclax, a mcl-1 antagonist, inhibits tumorigenesis in transgenic mouse and human xenograft models of prostate cancer

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2012
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Abstract
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 (Tgfbr2ColTKO). The Tgfbr2ColTKO prostate epithelia demonstrated down-regulation of luminal and basal differentiation markers, as well as Pten expression and up-regulation of Mcl-1. However, unlike in men, Tgfbr2ColTKO prostates exhibited no regression acutely after castration. The administration of Sabutoclax (BI-97C1), a pan-active Bcl-2 protein family antagonist mediated apoptosis in castrate-resistant PCa cells of Tgfbr2ColTKO mice and human subcutaneous, orthotopic, and intratibial xenograft PCa models. Interestingly, Sabutoclax had little apoptotic effect on benign prostate tissue in Tgfbr2ColTKO and wild-type mice. Sabutoclax was able to block c-Met activation, a critical axis in PCa metastatic progression. Further, Sabutoclax synergistically sensitized PC-3 cells to the cytotoxic effects of docetaxel (Taxotere). Together, these data suggest that Sabutoclax inhibits castrate-resistant PCa alone at the primary and bone metastatic site as well as support sensitivity to docetaxel treatment.
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ii2012neoplasia:sabutoclax, Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Roger S. Jackson, II;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
Journal ACS chemical neuroscience
Year 2012
DOI
10.1593/neo.12640
URL
http://www.sciencedirect.com/science/article/pii/S1476558612800996
Keywords
neoplasms Oncology including cancer and carcinogens tumors

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