Natural product myricetin is a pan-KDM4 inhibitor which with poly lactic-co-glycolic acid formulation effectively targets castration-resistant prostate cancer

• DOI: 10.1186/s12929-022-00812-3
• Publication Date: 2022-05-09T06:03:33Z
• Authors: Jai-Shin Liu; Wei-Kai Fang; Shan-Min Yang; Meng-Chen Wu; Tsan-Jan Chen; Chih-Ming Chen; Tung-Yueh Lin; Kai-Lun Liu; Chien-Ming Wu; Yun-Ching Chen; Chih-Pin Chuu; Ling-Yu Wang; Hsing-Pang Hsieh; Hsing-Jien Kung; Wen-Ching Wang
• Keywords: Myricetin; Enzalutamide

Castration-resistant prostate cancer (CRPC) with sustained androgen receptor (AR) signaling remains a critical clinical challenge, despite depletion therapy. The Jumonji C-containing histone lysine demethylase family 4 (KDM4) members, KDM4A‒KDM4C, serve as coactivators of AR to promote tumor growth in and are candidate therapeutic targets overcome mutations/alterations-mediated resistance CRPC.In this study, using structure-based approach, we identified natural product, myricetin, able block the demethylation 3 9 trimethylation by KDM4 members evaluated its effects on CRPC. A screening was employed search for product that inhibited KDM4B. Inhibition kinetics myricetin determined. cytotoxic effect various cells evaluated. combined enzalutamide, second-generation inhibitor toward C4-2B, CRPC cell line, assessed. To improve bioavailability, encapsulated poly lactic-co-glycolic acid (PLGA), US food drug administration (FDA)-approved material carriers, synthesized antitumor activity alone or enzalutamide vivo C4-2B xenografts.Myricetin potent α-ketoglutarate-type blocks KDM4s significantly reduced proliferation both androgen-dependent (LNCaP) androgen-independent (CWR22Rv1 C4-2B). synergistic detected combination enzalutamide. PLGA-myricetin, treatment showed greater than control group xenograft model. Tumor lower alone.These results suggest is pan-KDM4 exhibited cytotoxicity cells. Importantly, PLGA-encapsulated potentially effective