Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Br J Pharmacol. 2024 Nov;181(22):4658-4676. doi: 10.1111/bph.16501. Epub 2024 Aug 14.
Prostate cancer remains a major public health burden worldwide. Polo like kinase 4 (PLK4) has emerged as a promising therapeutic target in prostate cancer due to its key roles in cell cycle regulation and tumour progression. This study aims to develop and characterize the novel curcumin analogue NL13 as a potential therapeutic agent and PLK4 inhibitor against prostate cancer.
NL13 was synthesized and its effects were evaluated in prostate cancer cells and mouse xenograft models. Kinome screening and molecular modelling identified PLK4 as the primary target. Antiproliferative and proapoptotic mechanisms were explored via cell cycle, apoptosis, gene and protein analyses.
Compared with curcumin, NL13 exhibited much greater potency in inhibiting PC3 (IC, 3.51 μM vs. 35.45 μM) and DU145 (IC, 2.53 μM vs. 29.35 μM) prostate cancer cells viability and PLK4 kinase activity (2.32 μM vs. 246.88 μM). NL13 induced G2/M cell cycle arrest through CCNB1/CDK1 down-regulation and triggered apoptosis via caspase-9/caspase-3 cleavage. These effects were mediated by PLK4 inhibition, which led to the inactivation of the AKT signalling pathway. In mice, NL13 significantly inhibited tumour growth and modulated molecular markers consistent with in vitro findings, including decreased p-AKT and increased cleaved caspase-9/3.
NL13, a novel PLK4-targeted curcumin analogue, exerts promising anticancer properties against prostate cancer by disrupting the PLK4-AKT-CCNB1/CDK1 and apoptosis pathways. NL13 represents a promising new agent for prostate cancer therapy.
前列腺癌仍然是全球范围内的一个主要公共卫生负担。由于在细胞周期调控和肿瘤进展中的关键作用，丝氨酸/苏氨酸激酶 4（PLK4）已成为前列腺癌治疗的一个有前途的靶点。本研究旨在开发和表征新型姜黄素类似物 NL13，作为一种潜在的治疗剂和 PLK4 抑制剂，用于治疗前列腺癌。
合成 NL13，并在前列腺癌细胞和小鼠异种移植模型中评估其作用。通过激酶组筛选和分子建模确定 PLK4 为主要靶点。通过细胞周期、凋亡、基因和蛋白质分析探讨其抗增殖和促凋亡机制。
与姜黄素相比，NL13 对 PC3（IC50，3.51 μM 对 35.45 μM）和 DU145（IC50，2.53 μM 对 29.35 μM）前列腺癌细胞活力和 PLK4 激酶活性的抑制作用更强（2.32 μM 对 246.88 μM）。NL13 通过下调 CCNB1/CDK1 诱导 G2/M 细胞周期停滞，并通过 caspase-9/caspase-3 裂解引发细胞凋亡。这些作用是通过抑制 PLK4 介导的，导致 AKT 信号通路失活。在小鼠中，NL13 显著抑制肿瘤生长，并调节与体外发现一致的分子标志物，包括降低的 p-AKT 和增加的 cleaved caspase-9/3。
NL13 是一种新型的 PLK4 靶向姜黄素类似物，通过破坏 PLK4-AKT-CCNB1/CDK1 和凋亡途径，对前列腺癌表现出有希望的抗癌特性。NL13 代表了一种治疗前列腺癌的有前途的新药物。
