Sabutoclax, a Mcl-1 antagonist, inhibits tumorigenesis in transgenic mouse and human xenograft models of prostate cancer.
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.
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Roger S
RS
Jackson
William
W
Placzek
Ana
A
Fernandez
Shabnam
S
Ziaee
Chia-Yi
CY
Chu
Jun
J
Wei
John
J
Stebbins
Shinichi
S
Kitada
Gloria
G
Fritz
John C
JC
Reed
Leland W
LW
Chung
Maurizio
M
Pellecchia
Neil A
NA
Bhowmick
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D018450:Disease Progression; D000077143:Docetaxel; D004357:Drug Synergism; D006072:Gossypol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C550162:1,1',6,6',7,7'-hexahydroxy-3,3'-dimethyl-N5-(2-phenylpropyl)-N5'-(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide; D000970:Antineoplastic Agents; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D000077143:Docetaxel; D019859:Proto-Oncogene Proteins c-met; D006072:Gossypol