Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 21; pp. 8785 - 8790
• Main Authors: Dash, Rupesh, Azab, Belal, Quinn, Bridget A, Shen, Xuening, Wang, Xiang-Yang, Das, Swadesh K, Rahmani, Mohamed, Wei, Jun, Hedvat, Michael, Dent, Paul, Dmitriev, Igor P, Curiel, David T, Grant, Steven, Wu, Bainan, Stebbins, John L, Pellecchia, Maurizio, Reed, John C, Sarkar, Devanand, Fisher, Paul B
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24-05-2011; National Acad Sciences
• Subjects: Animals; antineoplastic activity; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Apoptosis - drug effects; autophagy; Biological Sciences; Cell death; Cell Line, Tumor; Cells; Cytokines; Cytotoxicity; Gene expression; Genetic Therapy - methods; Gossypol - analogs & derivatives; Gossypol - pharmacology; Gossypol - therapeutic use; growth retardation; human growth; Humans; interleukin-10; Interleukins - administration & dosage; Male; Medical treatment; melanoma; Mice; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Myeloid cells; neoplasm cells; patients; Prostate; Prostate cancer; prostate gland; prostatic neoplasms; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Small interfering RNA; staining; Toxicity; Transfection; transgenic animals; Tumors; Western blotting; Xenograft Model Antitumor Assays
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1100769108

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.