A comprehensive view on the fisetin impact on colorectal cancer in animal models: Focusing on cellular and molecular mechanisms

Flavonoids, including fisetin, have been linked to a reduced risk of colorectal cancer (CRC) and have potential therapeutic applications for the condition. Fisetin, a natural flavonoid found in various fruits and vegetables, has shown promise in managing CRC due to its diverse biological activities. It has been found to influence key cell signaling pathways related to inflammation, angiogenesis, apoptosis, and transcription factors. The results of this study demonstrate that fisetin induces colon cancer cell apoptosis through multiple mechanisms. It impacts the p53 pathway, leading to increased levels of p53 and decreased levels of murine double minute 2, contributing to apoptosis induction. Fisetin also triggers the release of important components in the apoptotic process, such as second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI and cytochrome c. Furthermore, fisetin inhibits the cyclooxygenase-2 and wingless-related integration site (Wnt)/epidermal growth factor receptor/nuclear factor kappa B signaling pathways, reducing Wnt target gene expression and hindering colony formation. It achieves this by regulating the activities of cyclin-dependent kinase 2 and cyclin-dependent kinase 4, reducing retinoblastoma protein phosphorylation, decreasing cyclin E levels, and increasing p21 levels, ultimately influencing E2 promoter binding factor 1 and cell division cycle 2 (CDC2) protein levels. Additionally, fisetin exhibits various effects on CRC cells, including inhibiting the phosphorylation of Y-box binding protein 1 and ribosomal S6 kinase, promoting the phosphorylation of extracellular signal-regulated kinase 1/2, and disrupting the repair process of DNA double-strand breaks. Moreover, fisetin serves as an adjunct therapy for the prevention and treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutant CRC, resulting in a reduction in phosphatidylinositol-3 kinase (PI3K) expression, Ak strain transforming phosphorylation, mTOR activity, and downstream target proteins in CRC cells with a PIK3CA mutation. These findings highlight the multifaceted potential of fisetin in managing CRC and position it as a promising candidate for future therapy development. Fisetin has been shown to exhibit significant impact on colorectal cancer (CRC) in animal models by targeting various cellular and molecular mechanisms. It inhibits the phosphorylation of Y-box binding protein 1 and ribosomal S6 kinase and promotes the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), thereby disrupting the repair process of DNA double-strand breaks and increasing the sensitivity of cancer cells to radiation. Fisetin also reduces the activity of matrix metalloproteinase-7, an enzyme associated with cancer progression, and modulates the ERK/mitogen-activated protein kinase (MAPK) pathways, which are crucial for cell proliferation, survival, and differentiation. Additionally, fisetin exhibits antioxidant properties and engages with redox-related signaling pathways such as nuclear factor kappa B, nuclear erythroid-related factor 2, phosphatidylinositol-3 kinase (PI3K)/Ak strain transforming, and MAPK, leading to apoptosis and inhibition of cell growth in CRC cells. In vivo studies have demonstrated that fisetin significantly suppresses tumor growth without inducing significant toxicity, providing a potential therapeutic strategy for CRC.image