Fisetin and 5-fluorouracil: Effective combination for PIK3CA-mutant colorectal cancer

Naghma Khan1,2, Farah Jajeh1, Emily L Eberhardt3

  • 1Department of Dermatology, University of Wisconsin-Madison, Madison, WI.

Insights

Fisetin, a dietary flavonoid, shows promise in preventing and treating colorectal cancer. It reduces tumor incidence and enhances 5-fluorouracil (5-FU) therapy efficacy, particularly in PIK3CA-mutant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Prevention

Background:

  • Colorectal cancer (CRC) arises from genetic alterations, notably PIK3CA mutations.
  • Current treatments like 5-fluorouracil (5-FU) have limited efficacy and significant side effects.
  • Dietary compounds offer potential for cancer prevention and adjuvant therapy.

Purpose of the Study:

  • To investigate the effects of fisetin, alone or with 5-FU, on colorectal cancer cell growth and tumorigenesis.
  • To explore the impact of fisetin and 5-FU on the PI3K/AKT/mTOR signaling pathway.
  • To evaluate fisetin as a preventive agent and adjuvant therapy for PIK3CA-mutant CRC.

Main Methods:

  • In vitro studies assessed cell viability, colony formation, and apoptosis in PIK3CA-mutant and wild-type colon cancer cells.
  • Western blotting analyzed protein expression and phosphorylation in the PI3K/AKT/mTOR and AMPK signaling pathways.
  • In vivo studies utilized ApcMin/+ mice with PI3K activation to evaluate fisetin and 5-FU effects on intestinal tumorigenesis.

Main Results:

  • Fisetin and 5-FU combination therapy downregulated PI3K/AKT/mTOR signaling and increased AMPKα phosphorylation in PIK3CA-mutant cells.
  • Fisetin significantly reduced tumor incidence in ApcMin/+ mice with PI3K activation.
  • Combined fisetin and 5-FU treatment decreased the overall number of intestinal tumors in the mouse model.

Conclusions:

  • Fisetin demonstrates strong potential as a preventive agent against intestinal tumorigenesis.
  • Fisetin can serve as an effective adjuvant therapy when combined with 5-FU for PIK3CA-mutant colorectal cancer.
  • This study highlights fisetin's therapeutic value in CRC, offering a novel approach to improve treatment outcomes.

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