Institute of Molecular and Cellular Biology and Department of Life Sciences, National Tsing-Hua University, Hsinchu, 30013, Taiwan.
Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu, 30015, Taiwan.
J Biomed Sci. 2022 May 9;29(1):29. 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.
尽管已经进行了雄激素剥夺治疗，但具有持续雄激素受体 (AR) 信号的去势抵抗性前列腺癌 (CRPC) 仍然是一个重大的临床挑战。包含 Jumonji C 的组蛋白赖氨酸去甲基酶家族 4 (KDM4) 成员 KDM4A-KDM4C 作为 AR 的关键共激活因子，促进前列腺癌肿瘤生长，是克服 CRPC 中 AR 突变/改变介导的耐药性的候选治疗靶点。
在这项研究中，我们使用基于结构的方法，鉴定了一种天然产物杨梅素，它能够阻断 KDM4 成员对组蛋白 3 赖氨酸 9 三甲基化的去甲基化，并评估了其对 CRPC 的影响。采用基于结构的筛选方法寻找抑制 KDM4B 的天然产物。测定杨梅素的抑制动力学。评估杨梅素对各种前列腺癌细胞的细胞毒性作用。评估杨梅素与第二代雄激素受体抑制剂恩扎卢胺联合使用对 C4-2B（一种 CRPC 细胞系）的效果。为了提高生物利用度，用聚乳酸-羟基乙酸共聚物 (PLGA) 包裹杨梅素，PLGA 是美国食品和药物管理局 (FDA) 批准的作为药物载体的材料，合成并评估其单独使用或与恩扎卢胺联合使用时在体内 C4-2B 异种移植中的抗肿瘤活性。
杨梅素被鉴定为一种有效的 α-酮戊二酸型抑制剂，可阻断 KDM4s 的去甲基化活性，并显著降低雄激素依赖性 (LNCaP) 和雄激素非依赖性 CRPC (CWR22Rv1 和 C4-2B) 的增殖。在 C4-2B 中检测到杨梅素和恩扎卢胺联合使用具有协同细胞毒性作用。PLGA-杨梅素、恩扎卢胺和联合治疗在 C4-2B 异种移植模型中的抗肿瘤活性明显高于对照组。与单独使用恩扎卢胺或杨梅素治疗相比，联合治疗的肿瘤生长明显降低。
这些结果表明，杨梅素是一种泛 KDM4 抑制剂，对 CRPC 细胞具有很强的细胞毒性。重要的是，PLGA 包裹的杨梅素与恩扎卢胺的联合应用可能对 CRPC 有效。
