Flavopiridol's effects on metastasis in KRAS mutant lung adenocarcinoma cells


DOĞAN TURAÇLI İ., Korkmaz F. D., Candar T., Ekmekci A.

JOURNAL OF CELLULAR BIOCHEMISTRY, vol.120, no.4, pp.5628-5635, 2019 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 120 Issue: 4
  • Publication Date: 2019
  • Doi Number: 10.1002/jcb.27846
  • Journal Name: JOURNAL OF CELLULAR BIOCHEMISTRY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.5628-5635
  • Keywords: apoptosis, flavopiridol, metastasis, non-small-cell lung cancer (NSCLC), proliferation, PHASE-II TRIAL, KINASE INHIBITOR, CARCINOMA-CELLS, RAS ONCOGENES, CYCLE ARREST, INDUCTION, APOPTOSIS, EXPRESSION, CDK4
  • Gazi University Affiliated: Yes

Abstract

Background There is still no clinically approved agent for mutant KRAS, which is the most common alteration in non-small-cell lung cancer (NSCLC). Flavopiridol is a semisynthetic flavonoid that inhibits cell growth through cyclin-dependent kinases in G1/S or G2/M of the cell cycle and induces apoptosis. In this study, we evaluated its effect on cellular apoptosis, survival, and metastasis mechanisms on KRAS mutant A549, Calu-1, and H2009 cell lines. Methods The cytotoxic effects of flavopiridol on NSCLC cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability test. The cells were treated with 200 and 400 nM flavopiridol, and, then, apoptosis, survival, and metastasis-related protein expressions were determined by Western blot analysis. The antimetastatic effects of flavopiridol were assessed by wound healing and Galectin-3 activity assay. Results Flavopiridol drastically affected toxicity in all KRAS mutant NSCLC cells at nanomolar concentrations. Also, it could efficiently inhibit wound healing and Galectin-3 activity in all the cells tested. However, the metastasis-related protein expressions did not reflect these obvious effects on blotting. p-Erk was activated as a cellular survival mechanism to escape apoptosis in all the cells tested. Conclusion Although there are many mechanisms that still need to be elucidated, flavopiridol can be used as a metastasis inhibitor and an apoptosis inducer in KRAS mutant NSCLC.