title: Hydrazinobenzoylcurcumin inhibits androgen receptor activity and growth of castration-resistant prostate cancer in mice.
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 androgen-regulated 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.
authors.affiliation: Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Sahn-Ho
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Bioinformatics Core, Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Indrani
authors.initials: I
authors.lastname: Datta
authors.affiliation: Bioinformatics Core, Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Levin
authors.affiliation: Biostatistics Core, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Dyson
authors.affiliation: Pharmacology Core, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, JNCASR, Bangalore, Karnataka, India.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kaypee
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, JNCASR, Bangalore, Karnataka, India.
authors.forename: M Mahadeva
authors.initials: MM
authors.lastname: Swamy
authors.affiliation: Department of Pathology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Nilesh
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Biotechnology, Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea.
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Mani
authors.initials: M
authors.lastname: Menon
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, JNCASR, Bangalore, Karnataka, India.
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Kundu
authors.affiliation: Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: G Prem-Veer
authors.initials: GP
authors.lastname: Reddy
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D011897:Random Allocation; D011944:Receptors, Androgen / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D011720:Pyrazoles; D011944:Receptors, Androgen; C000591373:hydrazinobenzoylcurcumin; D003474:Curcumin
keywords: CTK7A; androgen receptor; calmodulin; castration-resistant prostate cancer; hydrazinobenzoylcurcumin