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TLC388 Induces DNA Damage and G2 Phase Cell Cycle Arrest in Human Non-Small Cell Lung Cancer Cells

Authors
  • Wu, Kun-Ming1, 2, 3
  • Chi, Chih-Wen4, 5
  • Lai, Jerry Cheng-Yen6
  • Chen, Yu-Jen3, 4, 7, 8
  • Kou, Yu Ru1
  • 1 Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei
  • 2 Chest Division, Department of Internal Medicine, MacKay Memorial Hospital, Taipei
  • 3 Mackay Junior College of Medicine, Nursing, and Management, Taipei
  • 4 Department of Medical Research, MacKay Memorial Hospital, New Taipei
  • 5 Department of Nursing, MacKay Medical College, New Taipei
  • 6 Department of Medical Research, Taitung MacKay Memorial Hospital, Taipei
  • 7 Department of Medical Research, China Medical University Hospital, Taichung
  • 8 Department of Radiation Oncology, MacKay Memorial Hospital, Taipei
Type
Published Article
Journal
Cancer control : journal of the Moffitt Cancer Center
Publication Date
Apr 13, 2020
Volume
27
Issue
1
Identifiers
DOI: 10.1177/1073274819897975
PMID: 32281394
PMCID: PMC7154561
Source
PubMed Central
Keywords
License
Unknown

Abstract

TLC388, a camptothecin-derivative targeting topoisomerase I, is a potential anticancer drug. In this study, its effect on A549 and H838 human non-small cell lung cancer (NSCLC) cells was investigated. Cell viability and proliferation were determined by thiazolyl blue tetrazolium bromide and clonogenic assays, respectively, and cell cycle analysis and detection of phosphorylated histone H3 (Ser10) were performed by flow cytometry. γ-H2AX protein; G2/M phase-associated molecules ataxia-telangiectasia mutated (ATM), CHK1, CHK2, CDC25C, CDC2, and cyclin B1; and apoptosis were assessed with immunofluorescence staining, immunoblotting, and an annexin V assay, respectively. The effect of co-treatment with CHIR124 (a checkpoint kinase 1 [CHK1] inhibitor) was also studied. TLC388 decreased the viability and proliferation of cells of both NSCLC lines in a dose-dependent manner. TLC388 inhibited the viability of NSCLC cell lines with an estimated concentration of 50% inhibition (IC50), which was 4.4 and 4.1 μM for A549 and H838 cells, respectively, after 24 hours. Moreover, it resulted in the accumulation of cells at the G2/M phase and increased γ-H2AX levels in A549 cells. Levels of the G2 phase–related molecules phosphorylated ATM, CHK1, CHK2, CDC25C, and cyclin B1 were increased in TLC388-treated cells. CHIR124 enhanced the cytotoxicity of TLC388 toward A549 and H838 cells and induced apoptosis of the former. TLC388 inhibits NSCLC cell growth by inflicting DNA damage and activating G2/M checkpoint proteins that trigger G2 phase cell cycle arrest to enable DNA repair. CHIR124 enhanced the cytotoxic effect of TLC388 and induced apoptosis.

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