2. Academic Validation
  3. NL13, a novel curcumin analogue and polo like kinase 4 inhibitor, induces cell cycle arrest and apoptosis in prostate cancer models

NL13, a novel curcumin analogue and polo like kinase 4 inhibitor, induces cell cycle arrest and apoptosis in prostate cancer models

  • Br J Pharmacol. 2024 Aug 14. doi: 10.1111/bph.16501.
Xinyi Qiao 1 2 3 4 5,  Ke Zheng 1 2 3 4 5,  Lei Ye 1 2 3 4 5,  Jin Yang 1 2 3 4 5,  Rong Cui 1 2 3 4 5,  Yuanyuan Shan 5,  Xiaoheng Li 1 2 3 4,  Huitao Li 1 2 3 4,  Qiqi Zhu 1 2 3 4,  Zhiguang Zhao 5,  Ren-Shan Ge 1 2 3 4 5,  Yiyan Wang 1 2 3 4 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2 Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3 Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 4 Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, Wenzhou, Zhejiang, China.
  • 5 Department of Pathology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
PMID: 39142876 DOI: 10.1111/bph.16501
Abstract

Background and purpose: 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.

Experimental approach: 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.

Key results: Compared with curcumin, NL13 exhibited much greater potency in inhibiting PC3 (IC50, 3.51 μM vs. 35.45 μM) and DU145 (IC50, 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.

Conclusion and implications: 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.

Keywords

apoptosis; cell cycle; curcumin analogue; polo like kinase 4; prostate cancer.

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