Combination therapy of antiandrogen and XIAP inhibitor for treating advanced prostate cancer

Michael Danquah, Charles B. Duke, Renukadevi Patil, Duane D. Miller, Ram I. Mahato

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Purpose Overexpression of the androgen receptor (AR) and anti-apoptotic genes including X-linked inhibitor of apoptosis protein (XIAP) provide tumors with a proliferative advantage. Therefore, our objective was to determine whether novel antiandrogen (CBDIV17) and XIAP inhibitor based combination therapy can treat advanced prostate cancer. Methods CBDIV17 and embelin-6g were synthesized and their effect on cell proliferation, apoptosis, cell cycle and AR and XIAP gene silencing determined. Results CBDIV17 was more potent than bicalutamide and inhibited proliferation of C4-2 and LNCaP cells, IC50 for CBDIV17 was ~12 μM and ~21 μM in LNCaP and C4-2 cells, respectively, whereas bicalutamide had IC50 of ~46 μM in LNCaP cells and minimal effect in C4-2 cells. CBDIV17 induced apoptosis more effectively compared to bicalutamide and significantly inhibited DNA replication. Combination of CBDIV17 and embelin resulted in supra-additive antiproliferative and apoptotic effects. Embelin downregulated AR expression and decreased androgenmediated AR phosphorylation at Ser81. These hydrophobic drugs were solubilized using micelles prepared with polyethylene glycolb- poly (carbonate-co-lactide) (PEG-b-p(CB-co-LA)) copolymer. Combination therapy inhibited prostate tumor growth more effectively compared to control or monotherapy in vivo. Conclusions Our results demonstrated that CBDIV17 in combination with embelin can potentially treat advanced prostate cancer.

Original languageEnglish (US)
Pages (from-to)2079-2091
Number of pages13
JournalPharmaceutical Research
Volume29
Issue number8
DOIs
StatePublished - Aug 2012

Keywords

  • Androgen receptor
  • Antiandrogen
  • Bicalutamide
  • Embelin
  • Polymeric micelles
  • Prostate cancer
  • XIAP

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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