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

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 Apc Min/+ mice that also express constitutively active PI3K in the distal small intestine and colon. Tumor incidence was markedly lower in fisetin-treated FC 1 3K 1 Apc Min/+ 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.

Fisetin inhibits the proliferation, migration and invasion of pancreatic cancer by targeting PI3K/AKT/mTOR signaling

“…Fisetin (3,3’,4’,7-tetrahydroxyflavone), which distributes abundantly in vegetables, as well as fruits for instance cucumber, persimmon, and apple, was explored to possess antioxidant, anti-microbial, anti-cancer, as well as anti-inflammatory properties in recent studies [ 13 ]. For example, fisetin could dampen colorectal cancer cells growth in vitro along with in vivo [ 14 ] and display anti-cancer effects on laryngeal carcinoma [ 15 ]. However, there is no report about the anti-cancer influence of fisetin on PC.…”

Integrating Ethnobotany, Phytochemistry, and Pharmacology of Cotinus coggygria and Toxicodendron vernicifluum: What Predictions can be Made for the European Smoketree?

“…The combination determined inhibition of AKT phosphorylation and decreased PI3K (phosphatidylinositide-3-kinase) expression. A preventive effect against tumor formation was also observed for fisetin (Khan et al, 2019). Fisetin acts on oral squamous cell carcinoma by targeting PAK4 (p21-activated kinase 4).…”

Fisetin, a Potent Anticancer Flavonol Exhibiting Cytotoxic Activity against Neoplastic Malignant Cells and Cancerous Conditions: A Scoping, Comprehensive Review

“…FIS causes a decrease in the viability of colorectal cancer cells of the HCT116 and HT29 lines [47][48][49][50][51], LoVo [52], COLO205 [49,50,53], HT-29 [47,49,51,54] and HCT-15 [51]. It has also been shown that in the case of HCT-116 and HT-29 lines, FIS reduces the number of colonies, and this effect may be maximized by combining FIS with 5-fluorocuacil (5-FU) [47,50].…”