- 作者: 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
- 作者服務機構: 1.Biomedical Translation Research Center, Academia Sinica, Taipei, 11571, Taiwan 2.Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, University of California Davis Cancer Centre, Sacramento, CA, 95817, USA 3.Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu, 30015, Taiwan 4.Department of Chemistry, National Tsing Hua University, Hsinchu, 30013, Taiwan 5.Division of Medical Oncology, Chang Gung Memorial Hospital, Linkou, Taoyuan, 33305, Taiwan 6.Graduate Institute of Biomedical Sciences, Division of Biochemistry, Molecular and Cellular Biology, Chang Gung University, Taoyuan, 33302, Taiwan 7.Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, 11031, Taiwan 8.Institute of Biomedical Engineering, National Tsing-Hua University, Hsinchu, 30013, Taiwan 9.Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Maioli, 35053, Taiwan 10.Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan 11.Institute of Molecular and Cellular Biology and Department of Life Sciences, National Tsing-Hua University, Hsinchu, 30013, Taiwan 12.Jai-Shin Liu and Wei-Kai Fang contributed equally to this work
- 中文摘要:
- 英文摘要:
Background
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.
Methods
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.
Results
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.
Conclusions
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. - 中文關鍵字:
- 英文關鍵字: Myricetin, Castration-resistant prostate cancer, Histone lysine demethylase family 4 (KDM4), Poly lactic-coglycolic acid (PLGA), Enzalutamide