Specific Irreversible Cell-Cycle Arrest and Depletion of Cancer Cells Obtained by Combining Curcumin and the Flavonoids Quercetin and Fisetin

Genes (Basel). 2022 Jun 23;13(7):1125. doi: 10.3390/genes13071125.

Abstract

Background: Induced senescence could be exploited to selectively counteract the proliferation of cancer cells and target them for senolysis. We examined the cellular senescence induced by curcumin and whether it could be targeted by fisetin and quercetin, flavonoids with senolytic activity. Methods: Cell-cycle profiles, chromosome number and structure, and heterochromatin markers were evaluated via flow cytometry, metaphase spreads, and immunofluorescence, respectively. The activation of p21waf1/cip1 was assessed via RT-qPCR and immunoblotting. Senescent cells were detected via SA-β-Galactosidase staining. Results: We report that curcumin treatment specifically triggers senescence in cancer cells by inducing mitotic slippage and DNA damage. We show that curcumin-induced senescence is p21waf1/cip1-dependent and characterized by heterochromatin loss. Finally, we found that flavonoids clear curcumin-induced senescent cancer cells. Conclusions: Our findings expand the characterization of curcumin-induced cellular senescence in cancer cells and lay the foundation for the combination of curcumin and flavonoids as a possible anti-cancer therapy.

Keywords: DNA methylation; H3K9 trimethylation; SAHF; curcumin; fisetin; heterochromatin; quercetin; senescence; senolytics.

MeSH terms

  • Cell Cycle Checkpoints
  • Curcumin* / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Flavonoids / pharmacology
  • Flavonols
  • Heterochromatin
  • Neoplasms*
  • Quercetin / pharmacology

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Flavonoids
  • Flavonols
  • Heterochromatin
  • Quercetin
  • Curcumin
  • fisetin

Grant support

This research was partly funded by the University of Palermo (Italy) via grant numbers FFR-D15-005543 to A.D.L and FFR-D15-162553 to V.B. V.B. receives salary support under the program “Linea 2, Attrazione dei Ricercatori” launched by “PON Ricerca e Innovazione 2014–2020” and implemented by “Fondo Sociale Europeo” with the reference AIM 1808223-1.