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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.
Abstract:
The normal colon epithelium is transformed into its neoplastic counterpart through a series of genetic alterations in driver genes including activating mutations in PIK3CA. Treatment often involves surgery followed by 5-fluorouracil (5-FU) based therapy, which has limited efficiency and serious side effects. We sought to determine whether fisetin, a dietary flavonoid, alone or in combination with 5-FU affected tumorigenesis in the mammalian intestine. We first determined the effect of fisetin, 5-FU or their combination on PIK3CA-mutant and PIK3CA wild-type colon cancer cells by assessing cell viability, colony formation, apoptosis and effects on PI3K/AKT/mTOR signaling. Treatment of PIK3CA-mutant cells with fisetin and 5-FU reduced the expression of PI3K, phosphorylation of AKT, mTOR, its target proteins, constituents of mTOR signaling complex and this treatment increased the phosphorylation of AMPKα. We then determined whether fisetin and 5-FU together or singly affected tumorigenesis in ApcMin/+ mice that also express constitutively active PI3K in the distal small intestine and colon. Tumor incidence was markedly lower in fisetin-treated FC1 3K1 ApcMin/+ mice that also express constitutively active PI3K in distal small intestine and colon, as compared to control animals, indicating that fisetin is a strong preventive agent. In addition, the combination of fisetin and 5-FU also reduced the total number of intestinal tumors. Fisetin could be used as a preventive agent plus an adjuvant with 5-FU for the treatment of PIK3CA-mutant colorectal cancer.
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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