頁籤選單縮合
題 名 | Natural Product Myricetin Is a Pan-KDM4 Inhibitor Which with Poly Lactic-co-glycolic Acid Formulation Effectively Targets Castration-resistant Prostate Cancer |
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作 者 | 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; | 書刊名 | Journal of Biomedical Science |
卷 期 | 29 2022[民111] |
頁 次 | 頁(29)1-(29)13 |
分類號 | 415.878 |
關鍵詞 | Myricetin; Castration-resistant prostate cancer; Histone lysine demethylase family 4; KDM4; Poly lactic-co-glycolic acid; PLGA; Enzalutamide; |
語 文 | 英文(English) |
DOI | 10.1186/s12929-022-00812-3 |
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. |
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