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

• Published in: Journal of biomedical science Vol. 29; no. 1; p. 29
• Main Authors: Liu, Jai-Shin, Fang, Wei-Kai, Yang, Shan-Min, Wu, Meng-Chen, Chen, Tsan-Jan, Chen, Chih-Ming, Lin, Tung-Yueh, Liu, Kai-Lun, Wu, Chien-Ming, Chen, Yun-Ching, Chuu, Chih-Pin, Wang, Ling-Yu, Hsieh, Hsing-Pang, Kung, Hsing-Jien, Wang, Wen-Ching
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09.05.2022; BioMed Central; BMC
• Subjects: Androgen receptors; Androgens; Androgens - pharmacology; Androgens - therapeutic use; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Bioavailability; Biocompatibility; Biological Products - pharmacology; Biological Products - therapeutic use; Cancer therapies; Castration; Castration-resistant prostate cancer; Cell growth; Cell Line, Tumor; Cell Proliferation; Combined treatment; Computer software industry; Cytotoxicity; Demethylation; Depletion; Drug carriers; Drug delivery; Drug delivery systems; Drug dosages; Drug Resistance, Neoplasm; Drugs; Encapsulation; Enzalutamide; Enzymes; Evaluation; Flavonoids - pharmacology; Gene expression; Glycolates; Glycolic acid; Glycols - pharmacology; Glycols - therapeutic use; Health aspects; Histone lysine demethylase family 4 (KDM4); Histones; Humans; Inhibitors; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - pharmacology; Ketoglutaric acid; Kinases; Lysine; Male; Methylation; Mutation; Myricetin; Natural products; Nitriles - pharmacology; Nitriles - therapeutic use; Poly lactic-co-glycolic acid (PLGA); Polylactide-co-glycolide; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Receptors, Androgen - therapeutic use; Software; Therapeutic targets; Toxicity; Tumors; Vehicles; Xenografts; Xenotransplantation; United States; United States > US; Castration-resistant prostate cancer; Histone lysine demethylase family 4 (KDM4); Poly lactic-co-glycolic acid (PLGA); Enzalutamide; Myricetin
• ISSN: 1423-0127; 1021-7770; 1423-0127
• DOI: 10.1186/s12929-022-00812-3

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