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

Academic Article

Abstract

  • Resistance to available therapeutic agents has been a common problem thwarting progress in treatment of castrateresistant 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. © 2012 Neoplasia Press, Inc. All rights reserved.
  • Published In

  • Neoplasia  Journal
  • Digital Object Identifier (doi)

    Author List

  • Jackson RS; Placzek W; Fernandez A; Ziaee S; Chu CY; Wei J; Stebbins J; Kitada S; Fritz G; Reed JC
  • Start Page

  • 656
  • End Page

  • 665
  • Volume

  • 14
  • Issue

  • 7