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Combination Therapy of Antiandrogen and XIAP Inhibitor for Treating Advanced Prostate Cancer

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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 androgen-mediated AR phosphorylation at Ser81. These hydrophobic drugs were solubilized using micelles prepared with polyethylene glycol-b-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.

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ACKNOWLEDGMENTS & DISCLOSURES

This work is supported by an Idea Award (W81XWH-10-1-0969) 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) AccuTOF-D time-of-flight (TOF) mass spectrometer with a DART (direct analysis in real time) ionization source.

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Authors and Affiliations

  1. University of Tennessee Health Science Center, Department of Pharmaceutical Sciences, 19 South Manassas, CRB RM 224, Memphis, 38103-3308, Tennessee, USA

    Ram I. Mahato

  2. University of Tennessee Health Science Center, Department of Pharmaceutical Sciences, 19 South Manassas, CRB RM 226, Memphis, 38103-3308, Tennessee, USA

    Michael Danquah

  3. University of Tennessee Health Science Center, Department of Pharmaceutical Sciences, 327 Johnson Building, Memphis, 38163, Tennessee, USA

    Charles B. Duke III & Renukadevi Patil

  4. University of Tennessee Health Science Center, Department of Pharmaceutical Sciences, 435 Pharmacy Building, Memphis, 38163, Tennessee, USA

    Duane D. Miller

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  1. Michael Danquah
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  2. Charles B. Duke III
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  5. Ram I. Mahato
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Correspondence to Ram I. Mahato.

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Danquah, M., Duke, C.B., Patil, R. et al. Combination Therapy of Antiandrogen and XIAP Inhibitor for Treating Advanced Prostate Cancer. Pharm Res 29, 2079–2091 (2012). https://doi.org/10.1007/s11095-012-0737-1

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  • DOI: https://doi.org/10.1007/s11095-012-0737-1

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