| Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity. | |
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MedLine Citation:
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PMID: 21555592 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Limited options are available for treating patients with advanced prostate cancer (PC). Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), an IL-10 family cytokine, exhibits pleiotropic anticancer activities without adversely affecting normal cells. We previously demonstrated that suppression of the prosurvival Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1), is required for mda-7/IL-24-mediated apoptosis of prostate carcinomas. Here we demonstrate that pharmacological inhibition of Mcl-1 expression with the unique Apogossypol derivative BI-97C1, also called Sabutoclax, is sufficient to sensitize prostate tumors to mda-7/IL-24-induced apoptosis, whereas ABT-737, which lacks efficacy in inhibiting Mcl-1, does not sensitize mda-7/IL-24-mediated cytotoxicity. A combination regimen of tropism-modified adenovirus delivered mda-7/IL-24 (Ad.5/3-mda-7) and BI-97C1 enhances cytotoxicity in human PC cells, including those resistant to mda-7/IL-24 or BI-97C1 alone. The combination regimen causes autophagy that facilitates NOXA- and Bim-induced and Bak/Bax-mediated mitochondrial apoptosis. Treatment with Ad.5/3-mda-7 and BI-97C1 significantly inhibits the growth of human PC xenografts in nude mice and spontaneously induced PC in Hi-myc transgenic mice. Tumor growth inhibition correlated with increased TUNEL staining and decreased Ki-67 expression in both PC xenografts and prostates of Hi-myc mice. These findings demonstrate that pharmacological inhibition of Mcl-1 with the Apogossypol derivative, BI-97C1, sensitizes human PCs to mda-7/IL-24-mediated cytotoxicity, thus potentially augmenting the therapeutic benefit of this combinatorial approach toward PC. |
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Authors:
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Rupesh Dash; Belal Azab; Bridget A Quinn; Xuening Shen; Xiang-Yang Wang; Swadesh K Das; Mohamed Rahmani; Jun Wei; Michael Hedvat; Paul Dent; Igor P Dmitriev; David T Curiel; Steven Grant; Bainan Wu; John L Stebbins; Maurizio Pellecchia; John C Reed; Devanand Sarkar; Paul B Fisher |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-05-09 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 108 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-05-25 Completed Date: 2011-10-07 Revised Date: 2012-04-10 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 8785-90 Citation Subset: IM |
Affiliation:
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Department of Human and Molecular Genetics, Virginia Commonwealth University Institute of Molecular Medicine, and Virginia Commonwealth University Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Combined Chemotherapy Protocols / pharmacology* Apoptosis / drug effects* Cell Line, Tumor Gene Therapy / methods* Gossypol / analogs & derivatives*, pharmacology, therapeutic use Humans Interleukins / administration & dosage Male Mice Mice, Nude Prostatic Neoplasms / drug therapy*, pathology, therapy Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors* Transfection Xenograft Model Antitumor Assays |
| Grant Support | |
ID/Acronym/Agency:
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P01 CA104177/CA/NCI NIH HHS; R01 CA097318/CA/NCI NIH HHS; R01 CA097318-10/CA/NCI NIH HHS; R01 CA127641/CA/NCI NIH HHS; R01 CA127641-04/CA/NCI NIH HHS; R01 CA149668/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/1,1',6,6',7,7'-hexahydroxy-3,3'-dimethyl-N5-(2-phenylpropyl)-N5'-(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide; 0/Interleukins; 0/Proto-Oncogene Proteins c-bcl-2; 0/apogossypol; 0/interleukin-24; 0/myeloid cell leukemia sequence 1 protein; 303-45-7/Gossypol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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