CCL299, a Benzimidazole Derivative Induces G1 Phase Arrest and Apoptosis in Cancer Cells

Anticancer Res. 2021 Feb;41(2):699-706. doi: 10.21873/anticanres.14821.

Abstract

Background/aim: Benzimidazoles are considered potential anticancer candidates. We herein studied the anticancer activity of CCL299, 4-(1H-1,3-benzodiazol-1-yl) benzonitrile.

Materials and methods: In this in vitro study, we used ATP assays, flow cytometry, western blotting, and caspase-3/7 assays to evaluate the effects of CCL299 on cell proliferation, cell-cycle progression and apoptosis.

Results: ATP assays showed that CCL299 inhibited cell growth in the hepatoblastoma cell line HepG2 and the cervical cancer cell line HEp-2, without exhibiting cytotoxic effects on non-cancer cells and TIG-1-20 fibroblasts. Flow cytometry, western blotting, and caspase-3/7 assays revealed that CCL299 induced G1-phase cell-cycle arrest followed by apoptosis that was associated with up-regulation of p-p53 (Ser15) and p21 expression and the down-regulation of p-CDK2 (Thr160) expression.

Conclusion: CCL299 exhibits cytotoxic activity via apoptosis in a subset of cancer cells, and should be considered as a promising anticancer candidate agent.

Keywords: Benzimidazole; CDK2; G1 phase arrest; apoptosis; p21; p53.

MeSH terms

  • A549 Cells
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Benzimidazoles / pharmacology*
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects*
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Signal Transduction
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Benzimidazoles
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • CASP3 protein, human
  • CASP7 protein, human
  • Caspase 3
  • Caspase 7