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Title of Journal: Pharm Res

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Abbravation: Pharmaceutical Research

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Springer US

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DOI

10.1002/asna.200710887

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1573-904X

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Combination Therapy of Antiandrogen and XIAP Inhib

Authors: Michael Danquah Charles B Duke Renukadevi Patil Duane D Miller Ram I Mahato
Publish Date: 2012/03/27
Volume: 29, Issue: 8, Pages: 2079-2091
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Abstract

Overexpression of the androgen receptor AR and antiapoptotic genes including Xlinked 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 cancerCBDIV17 was more potent than bicalutamide and inhibited proliferation of C42 and LNCaP cells IC50 for CBDIV17 was ∼12 μM and ∼21 μM in LNCaP and C42 cells respectively whereas bicalutamide had IC50 of ∼46 μM in LNCaP cells and minimal effect in C42 cells CBDIV17 induced apoptosis more effectively compared to bicalutamide and significantly inhibited DNA replication Combination of CBDIV17 and embelin resulted in supraadditive 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 glycolbpoly carbonatecolactide PEGbpCBcoLA copolymer Combination therapy inhibited prostate tumor growth more effectively compared to control or monotherapy in vivoThis work is supported by an Idea Award W81XWH1010969 from the Department of Defense Prostate Cancer Research Program We would also like to thank Dr Liguo Song for his help in obtaining HRMS data Molecular weight measurement was performed at the Mass Spectrometry Center of the Department of Chemistry at the University of Tennessee at Knoxville using a JEOL Peabody MA AccuTOFD timeofflight TOF mass spectrometer with a DART direct analysis in real time ionization source

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