Document Detail


Sabutoclax, a Mcl-1 antagonist, inhibits tumorigenesis in transgenic mouse and human xenograft models of prostate cancer.
MedLine Citation:
PMID:  22904682     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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; 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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  14     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-08-20     Completed Date:  2013-03-18     Revised Date:  2014-04-16    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  656-65     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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
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
Grant Support
ID/Acronym/Agency:
CA098912/CA/NCI NIH HHS; CA108646/CA/NCI NIH HHS; CA113318/CA/NCI NIH HHS; CA149668/CA/NCI NIH HHS; P30 CA030199/CA/NCI NIH HHS; R01 CA149668/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/1,1',6,6',7,7'-hexahydroxy-3,3'-dimethyl-N5-(2-phenylpropyl)-N5'-(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide; 0/Antineoplastic Agents; 0/Mcl1 protein, mouse; 0/Myeloid Cell Leukemia Sequence 1 Protein; 0/Proto-Oncogene Proteins c-bcl-2; 0/Taxoids; 15H5577CQD/docetaxel; EC 2.7.10.1/Proto-Oncogene Proteins c-met; KAV15B369O/Gossypol
Comments/Corrections

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