title: Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity.
abstract: 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.
authors.affiliation: 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.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Belal
authors.initials: B
authors.lastname: Azab
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Quinn
authors.forename: Xuening
authors.initials: X
authors.lastname: Shen
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Mohamed
authors.initials: M
authors.lastname: Rahmani
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Michael
authors.initials: M
authors.lastname: Hedvat
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Igor P
authors.initials: IP
authors.lastname: Dmitriev
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Bainan
authors.initials: B
authors.lastname: Wu
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007378:Interleukins / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
chemical_list: D006072:Gossypol; D007378:Interleukins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D000099180:Interleukin-24; C550162:1,1',6,6',7,7'-hexahydroxy-3,3'-dimethyl-N5-(2-phenylpropyl)-N5'-(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide; C579094:Mcl1 protein, mouse; C492806:apogossypol