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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.
AuthorsRupesh 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
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 21 Pg. 8785-90 (May 24 2011) ISSN: 1091-6490 [Electronic] United States
PMID21555592 (Publication 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.)
Chemical References
  • 1,1',6,6',7,7'-hexahydroxy-3,3'-dimethyl-N5-(2-phenylpropyl)-N5'-(2-phenylpropyl)-2,2'-binaphthyl-5,5'-dicarboxamide
  • Interleukins
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • apogossypol
  • interleukin-24
  • Gossypol
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Genetic Therapy (methods)
  • Gossypol (analogs & derivatives, pharmacology, therapeutic use)
  • Humans
  • Interleukins (administration & dosage)
  • Male
  • Mice
  • Mice, Nude
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Prostatic Neoplasms (drug therapy, pathology, therapy)
  • Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
  • Transfection
  • Xenograft Model Antitumor Assays

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