Hydrazinobenzoylcurcumin inhibits androgen receptor activity and growth of castration-resistant prostate cancer in mice

Min Wu, Sahn Ho Kim, Indrani Datta, Albert Levin, Gregory Dyson, Jing Li, Stephanie Kaypee, M. Mahadeva Swamy, Nilesh Gupta, Ho Jeong Kwon, Mani Menon, Tapas K. Kundu, G. Prem Veer Reddy

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Abstract

There is a critical need for therapeutic agents that can target the amino-terminal domain (NTD) of androgen receptor (AR) for the treatment of castration-resistant prostate cancer (CRPC). Calmodulin (CaM) binds to the AR NTD and regulates AR activity. We discovered that Hydrazinobenzoylcurcumin (HBC), which binds exclusively to CaM, inhibited AR activity. HBC abrogated AR interaction with CaM, suppressed phosphorylation of AR Serine81, and blocked the binding of AR to androgen-response elements. RNA-Seq analysis identified 57 androgen-regulated genes whose expression was significantly (p ≤ 0.002) altered in HBC treated cells as compared to controls. Oncomine analysis revealed that genes repressed by HBC are those that are usually overexpressed in prostate cancer (PCa) and genes stimulated by HBC are those that are often down-regulated in PCa, suggesting a reversing effect of HBC on androgenregulated gene expression associated with PCa. Ingenuity Pathway Analysis revealed a role of HBC affected genes in cellular functions associated with proliferation and survival. HBC was readily absorbed into the systemic circulation and inhibited the growth of xenografted CRPC tumors in nude mice. These observations demonstrate that HBC inhibits AR activity by targeting the AR NTD and suggest potential usefulness of HBC for effective treatment of CRPC.

Original languageEnglish
Pages (from-to)6136-6150
Number of pages15
JournalOncotarget
Volume6
Issue number8
DOIs
Publication statusPublished - 2015 Jan 1

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All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Wu, M., Kim, S. H., Datta, I., Levin, A., Dyson, G., Li, J., Kaypee, S., Mahadeva Swamy, M., Gupta, N., Kwon, H. J., Menon, M., Kundu, T. K., & Reddy, G. P. V. (2015). Hydrazinobenzoylcurcumin inhibits androgen receptor activity and growth of castration-resistant prostate cancer in mice. Oncotarget, 6(8), 6136-6150. https://doi.org/10.18632/oncotarget.3346