Fisetin and hesperetin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling

Tumour Biol. 2016 May;37(5):5781-95. doi: 10.1007/s13277-015-4118-3. Epub 2015 Sep 25.


Fisetin and hesperetin, naturally occurring flavonoids, have been reported as novel antioxidants with chemopreventive/chemotherapeutic potential against various types of cancer. However, their mechanism of action in CML is still unknown. This particular study aims to evaluate the therapeutic potentials of fisetin and hesperetin and their effects on cell proliferation, apoptosis, and cell cycle progression in human K562 CML cells. The results indicated that fisetin and hesperetin inhibited cell proliferation and triggered programmed cell death in these cells. The latter was confırmed by mitochondrial membrane depolarization and an increase in caspase-3 activation. In addition to that, we have detected S and G2/M cell cycle arrests and G0/G1 arrest upon fisetin and hesperetin treatment, respectively. To identify the altered genes and genetic networks in response to fisetin and hesperetin, whole-genome microarray analysis was performed. The microarray gene profiling analysis revealed some important signaling pathways including JAK/STAT pathway, KIT receptor signaling, and growth hormone receptor signaling that were altered upon fisetin and hesperetin treatment. Moreover, microarray data suggested potential candidate genes for targeted CML therapy. Fisetin and hesperetin significantly modulated the expression of genes involved in cell proliferation and division, apoptosis, cell cycle regulation, and other significant cellular processes such as replication, transcription, and translation. In conclusion, our results suggest that fisetin and hesperetin as potential natural agents for CML therapy.

Keywords: Apoptosis; Chronic myeloid leukemia; Fisetin; Gene profiling; Hesperetin.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Flavonoids / pharmacology*
  • Flavonols
  • Gene Expression Regulation, Leukemic / drug effects
  • Gene Regulatory Networks
  • Genome-Wide Association Study
  • Hesperidin / pharmacology*
  • Humans
  • K562 Cells / drug effects
  • Membrane Potential, Mitochondrial / drug effects
  • Neoplasm Proteins / metabolism


  • Antineoplastic Agents, Phytogenic
  • Flavonoids
  • Flavonols
  • Neoplasm Proteins
  • Hesperidin
  • CASP3 protein, human
  • Caspase 3
  • fisetin
  • hesperetin