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  3. PI3K/mTOR inhibitor VS-5584 combined with PLK1 inhibitor exhibits synergistic anti-cancer effects on non-small cell lung cancer

PI3K/mTOR inhibitor VS-5584 combined with PLK1 inhibitor exhibits synergistic anti-cancer effects on non-small cell lung cancer

  • Eur J Pharmacol. 2023 Aug 23;176004. doi: 10.1016/j.ejphar.2023.176004.
Senxia Zhao 1,  Yibin Li 1,  Gang Li 1,  Juanping Ye 1,  Rong Wang 2,  Xiaoting Zhang 1,  Fei Li 1,  Chang Gao 1,  Junbiao Li 1,  Jie Jiang 3,  Yanjun Mi 4
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research, The First Affiliated Hospital of Xiamen University, School of Clinical Medicine, Xiamen University, Xiamen, 361003, Fujian Province, PR China.
  • 2 Department of Thoracic Surgery, Xiamen Key Laboratory of Thoracic Tumor Diagnosis and Treatment, Institute of Lung Cancer, The First Affiliated Hospital of Xiamen University, School of Clinical Medicine, Xiamen University, Xiamen, 361003, Fujian Province, PR China.
  • 3 Department of Thoracic Surgery, Xiamen Key Laboratory of Thoracic Tumor Diagnosis and Treatment, Institute of Lung Cancer, The First Affiliated Hospital of Xiamen University, School of Clinical Medicine, Xiamen University, Xiamen, 361003, Fujian Province, PR China. Electronic address: Jiejiangfy@163.com.
  • 4 Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research, The First Affiliated Hospital of Xiamen University, School of Clinical Medicine, Xiamen University, Xiamen, 361003, Fujian Province, PR China. Electronic address: Miyj77@xmu.edu.cn.
PMID: 37625683 DOI: 10.1016/j.ejphar.2023.176004
Abstract

Small molecule drugs are of significant importance in the treatment of non-small cell lung Cancer (NSCLC). Here, we explored biological effects of the PI3K/mTOR Inhibitor VS-5584 on NSCLC. Our findings indicated that VS-5584 administration resulted in a dose-dependent inhibition of NSCLC cell proliferation, as well as the induction of Apoptosis and cycle arrest. Additionally, we observed a significant increase in intracellular Reactive Oxygen Species (ROS) levels following VS-5584 treatment. The use of the ROS inhibitor N-acetylcysteine (NAC) effectively reduced ROS levels and decreased the proportion of apoptotic cells. Treatment with VS-5584 led to an upregulation of genes associated with Apoptosis and cell cycle, such as c-caspase3 and P21. Conversely, a downregulation of cyclin-dependent kinase 1 (CDK1) expression was observed. Next, transcriptome analyses revealed that VS-5584 treatment altered the abundance of 1520 genes/transcripts in PC-9 cells, one of which was polo-like kinase 1 (PLK1). These differentially expressed genes were primarily enriched in biological processes such as cell cycle regulation and cell Apoptosis, which are closely linked to the P53 and Apoptosis pathways. Co-treatment with VS-5584 and PLK1 Inhibitor NMS-P937 resulted in enhanced Cancer cell death, exhibiting synergistic inhibitory activity. Notably, VS-5584 inhibited the growth of NSCLC in a patient-derived xenograft (PDX) mouse model without observable abnormalities in major organs. Overall, VS-5584 effectively suppressed the growth of NSCLC cells both in vitro and in vivo. VS-5584 combined with NMS-P937 exhibited a synergistic effect in inhibiting NSCLC cell growth. These findings suggest that VS-5584 has potential as a therapeutic strategy for treating NSCLC.

Keywords

Antitumor effect; Non-small cell lung cancer; PI3K/mTOR; PLK1 inhibitor; VS-5584.

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