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

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 (Tgfbr2(ColTKO)). The Tgfbr2(ColTKO) 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, Tgfbr2(ColTKO) 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 Tgfbr2(ColTKO) mice and human subcutaneous, orthotopic, and intratibial xenograft PCa models. Interestingly, Sabutoclax had little apoptotic effect on benign prostate tissue in Tgfbr2(ColTKO) 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.

• Authors: Roger S Jackson 2nd, 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: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 14 Issue 7 Pg. 656-65 (Jul 2012) ISSN: 1476-5586 [Electronic] United States
• PMID: 22904682 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 1,1',6,6',7,7'-hexahydroxy-3,3'-dimethyl-N5-(2-phenylpropyl)-N5'-(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide
• Antineoplastic Agents
• Mcl1 protein, mouse
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Taxoids
• Docetaxel
• Proto-Oncogene Proteins c-met
• Gossypol

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology, therapeutic use)
• Apoptosis (drug effects, genetics)
• Bone Neoplasms (drug therapy, metabolism, secondary)
• Cell Transformation, Neoplastic (drug effects, metabolism)
• Disease Progression
• Docetaxel
• Drug Synergism
• Gossypol (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Humans
• Male
• Mice
• Mice, Transgenic
• Myeloid Cell Leukemia Sequence 1 Protein
• Orchiectomy
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-met (metabolism)
• Signal Transduction (drug effects)
• Taxoids (administration & dosage, pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays