Sabutoclax, a Mcl-1 Antagonist, Inhibits Tumorigenesis in Transgenic Mouse and Human Xenograft Models of Prostate Cancer12
| Autor: | Jackson, Roger S, Placzek, William, Fernandez, Ana, Ziaee, Shabnam, Chu, Chia-Yi, Wei, Jun, Stebbins, John, Kitada, Shinichi, Fritz, Gloria, Reed, John C, Chung, Leland W, Pellecchia, Maurizio, Bhowmick, Neil A |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Gossypol Prostatic Neoplasms Antineoplastic Agents Apoptosis Bone Neoplasms Drug Synergism Mice Transgenic Docetaxel Proto-Oncogene Proteins c-met Xenograft Model Antitumor Assays Tumor Burden Mice Cell Transformation Neoplastic Proto-Oncogene Proteins c-bcl-2 Disease Progression Animals Humans Myeloid Cell Leukemia Sequence 1 Protein Taxoids Orchiectomy Research Article Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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