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

作者：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.^*

来源：Proceedings of the National Academy of Sciences, 2011, 108(21): 8785-8790.

DOI：10.1073/pnas.1100769108

• BCL-2 FAMILY PROTEINS
• MELANOMA DIFFERENTIATION
• BH3-ONLY PROTEINS
• APOPTOSIS
• INHIBITOR
• INDUCTION
• CARCINOMA
• BCL-X(L)
• PATHWAYS
• DELIVERY

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 mda7/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.

• 出版日期2011-5-24