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.

A curcumin derivative hydrazinobenzoylcurcumin suppresses stem‐like features of glioblastoma cells by targeting Ca2+/calmodulin‐dependent protein kinase II

“…26,28,29 HBC directly binds to the C-terminal hydrophobic pocket of CaM in a Ca 2+ -dependent manner and thus downregulates Ca 2+ /CaM-dependent proliferative and proangiogenic signaling pathways. 26,28,29 HBC directly binds to the C-terminal hydrophobic pocket of CaM in a Ca 2+ -dependent manner and thus downregulates Ca 2+ /CaM-dependent proliferative and proangiogenic signaling pathways.…”

“…22,23 Although curcumin has been suggested as an anticancer drug, low stability and bioavail-ability limit its application. 26,27 HBC also caused both autophage and apoptosis in lung cancer cells. A recently developed synthetic curcumin derivative hydrazinobenzoylcurcumin (HBC) has shown a potent inhibitory effect on the proliferation of several human tumor cell lines via antagonization of the Ca 2+ /CaM function.…”

Epigenetic modulators as therapeutic targets in prostate cancer

“…CTK7A targets AR amino-terminal domain leading to its inhibition and to decreased proliferation of androgen-sensitive and castration-resistant AR-positive PCa cells. Moreover, it suppressed tumor growth in a xenograft model of CRPC [ 239 ]. Anacardic acid decreased cell proliferation and induced G1/S cell cycle arrest and apoptosis of LNCaP cells.…”

Castration-resistant prostate cancer: Androgen receptor inactivation induces telomere DNA damage, and damage response inhibition leads to cell death

“…In order to test the effect of AR antagonist ENZ and ATM inhibitor KU59403 (Medkoo Bioscience, NC) on 22Rv1 tumors, athymic nude mice (Charles River) were inoculated subcutaneously with 4 × 10 6 22Rv1 cells as described by Wu et al(27), and when tumor size reached about 200 mm 3 , tumor-bearing mice were randomly assigned to the following 4 treatment groups: vehicle (control, 6 mice), ENZ (enzalutamide, Selleckchem, TX) alone (7 mice); ATMi KU59403 alone (7 mice); ENZ + KU59403 (6 mice). All treatments were carried out 5 days/week for 4 weeks.…”