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lüll Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity Dash R; Azab B; Quinn BA; Shen X; Wang XY; Das SK; Rahmani M; Wei J; Hedvat M; Dent P; Dmitriev IP; Curiel DT; Grant S; Wu B; Stebbins JL; Pellecchia M; Reed JC; Sarkar D; Fisher PBProc Natl Acad Sci U S A 2011[May]; 108 (21): 8785-90Limited 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.|Animals[MESH]|Antineoplastic Combined Chemotherapy Protocols/*pharmacology[MESH]|Apoptosis/*drug effects[MESH]|Cell Line, Tumor[MESH]|Genetic Therapy/*methods[MESH]|Gossypol/*analogs & derivatives/pharmacology/therapeutic use[MESH]|Humans[MESH]|Interleukins/administration & dosage[MESH]|Male[MESH]|Mice[MESH]|Mice, Nude[MESH]|Myeloid Cell Leukemia Sequence 1 Protein[MESH]|Prostatic Neoplasms/*drug therapy/pathology/therapy[MESH]|Proto-Oncogene Proteins c-bcl-2/*antagonists & inhibitors[MESH]|Transfection[MESH]|Xenograft Model Antitumor Assays[MESH] |