Fisetin cancer research has revealed promising therapeutic effects of this naturally occurring flavonoid found in various fruits and vegetables. Fisetin has gained significant attention for its potential roles in cancer therapy, prevention, and inhibition of tumor growth. It possesses anticancer activity against various cancer types, including melanoma, pancreatic, prostate, colorectal, breast, liver, and nasopharyngeal cancers. This article, presented by Hygieia Biotech, delves into the effect of fisetin on various cancer cell lines and its mechanisms in inducing cancer cell death, highlighting its potential as a natural agent against multiple cancer types.
Introduction to Fisetin
Fisetin is a naturally occurring flavonoid present in a variety of fruits and vegetables, including strawberries, grapes, apples, and onions. Recognized for its antioxidant and anti-inflammatory properties, fisetin has attracted considerable scientific interest for its potential health benefits, particularly in the context of cancer therapy. This flavonoid occurs naturally in various dietary sources such as strawberries, apples, and persimmons. Notably, the highest concentration of fisetin is found in strawberries, where it is approximately 160 µg/g. The effect of fisetin on cancer cells has been widely studied, revealing its ability to target multiple aspects of cancer cell biology.
One of the most notable effects of fisetin is its capacity to induce apoptosis, or programmed cell death, in cancer cells. Research has shown that fisetin induced apoptosis in various cancer cell lines, such as prostate cancer cells, pancreatic cancer cells, and breast cancer cells. Fisetin prompts apoptosis by avoiding cancer cell division related to the activation of caspase-9 and caspase-8. In addition to promoting cell death, fisetin can inhibit cell proliferation, effectively slowing the growth and spread of cancer cells. These actions are mediated through the modulation of key cell signaling pathways that regulate cell survival, division, and death.
Fisetin’s impact is not limited to a single cancer type; it has demonstrated efficacy across a range of cancer cell lines, making it a versatile candidate for cancer therapy. By influencing signaling pathways and inducing both apoptosis and autophagy, fisetin offers a multifaceted approach to combating cancer. Additionally, fisetin may enhance the effectiveness of chemotherapy while reducing toxic side effects. Its ability to inhibit cell proliferation and promote cancer cell death underscores its promise as a natural compound for cancer prevention and treatment.
The Effect of Fisetin on Cancer Cells
Research shows that fisetin exerts a profound effect on cancer cells by inhibiting their proliferation and inducing programmed cell death. Fisetin treatment has been demonstrated to reduce cell growth and viability in a dose-dependent manner across different cancer cell lines, including prostate cancer cells, pancreatic cancer cells, breast cancer cells, and gastric cancer cells. Studies often use human cancer cells to evaluate the effects of fisetin, analyzing their molecular and cellular responses to treatment. Notably, fisetin induces apoptosis—a form of programmed cell death—in these tumor cells, effectively reducing their survival and ability to proliferate. Fisetin induces apoptosis in caspase-3-deficient MCF-7 breast cancer cells by activating caspase-7, -8, and -9.
The impact of fisetin on cancer cell lines is multifaceted. For example, in human pancreatic cancer cells, fisetin induces autophagic cell death, complementing apoptosis by degrading damaged cellular components and enhancing cancer cell death. In these experimental setups, cells were treated with fisetin and compared to control cells to assess changes in viability and apoptosis. Similarly, in breast cancer cell lines, particularly triple-negative breast cancer cells, fisetin treatment inhibits cell proliferation and promotes apoptosis, offering hope for tackling aggressive cancer subtypes. Notably, fisetin induces double-strand breaks (DSB) in triple-negative breast cancer (TNBC) cells, further contributing to its anticancer effects. Additionally, fisetin interferes with classical non-homologous end joining and homologous recombination repair pathways to inhibit the repair of DNA double-strand breaks. Molecular responses observed in fisetin-treated cells include increased autophagy, induction of apoptosis, and modulation of key signaling pathways.
Cell Cycle Arrest and Signaling Pathways
One critical mechanism by which fisetin exerts its anticancer effects is through the induction of cell cycle arrest. Fisetin induces cell cycle arrest at specific phases, halting the progression of the cell cycle in cancer cells and preventing their division. Fisetin helps in the downregulation of approximately 27 genes involved in critical functions of the G2/M phase. Additionally, fisetin successfully inhibits the kinase activity of significant cell cycle regulatory molecules, such as CDK6. This interruption leads to reduced cell viability and increased susceptibility to cell death. The effect of fisetin is mediated through activation and modulation of SEMA3E, CDKN1A, GADD45A, and GADD45B genes.
Moreover, fisetin influences several key cell signaling pathways involved in cancer cell survival and proliferation. Notably, fisetin modulates the PI3K/AKT/mTOR pathway, a crucial regulator of cell growth and metabolism frequently dysregulated in cancer. The antiproliferative effect of fisetin involves modulation of multiple signaling pathways, including CDK5 signaling and ERK/MAPK signaling. By inhibiting this pathway, fisetin disrupts survival signals within tumor cells, leading to decreased cell proliferation and enhanced apoptosis.
Additionally, fisetin impacts the NF-κB signaling pathway, which plays a significant role in inflammation, cell survival, and cancer progression. Suppression of NF-κB by fisetin contributes to reduced expression of vascular endothelial growth factor (VEGF), thereby inhibiting angiogenesis and tumor growth. Fisetin inhibits microtubule assembly, leading to disruption in cell proliferation, invasion, and migration mechanisms in various cancer types. This multifaceted modulation of signaling pathways underscores fisetin’s potential as a comprehensive anticancer agent.
Fisetin Induced Autophagy
Fisetin-induced autophagy is an important mechanism by which this flavonoid exerts its anticancer effects. Autophagy is a cellular process that enables cells to degrade and recycle damaged or dysfunctional components, which can ultimately lead to cell death in cancer cells. Studies have shown that fisetin induces DNA double-strand breaks, which lead to chromosomal aberrations in tumor cells. Fisetin induces autophagy in various cancer cell lines, including pancreatic cancer cells and prostate cancer cells, contributing to the reduction of tumor cell viability.
The induction of autophagy by fisetin is closely linked to the activation and modulation of several cell signaling pathways, particularly the PI3K/AKT/MTOR pathway. This pathway plays a central role in regulating cell growth, survival, and metabolism, and its dysregulation is commonly observed in cancer. By targeting the PI3K/AKT/MTOR signaling cascade, fisetin disrupts the survival mechanisms of cancer cells, promoting autophagic cell death and enhancing the overall effect of fisetin in cancer treatment.
Fisetin-induced autophagy has been observed in a dose-dependent manner across different cancer cell lines, highlighting its potential as a therapeutic strategy. By leveraging both apoptosis and autophagy, fisetin offers a dual approach to eliminating cancer cells and inhibiting tumor progression.
Fisetin’s Role in Specific Cancer Types
Prostate Cancer
In prostate cancer cells, fisetin treatment shows promising results by inducing apoptosis and inhibiting cell proliferation. Studies highlight that fisetin not only induces cell cycle arrest but also reduces tumor progression, making it a valuable candidate for prostate cancer therapy.
Pancreatic Cancer
Pancreatic cancer, known for its poor prognosis, has been a focus of fisetin research. Human pancreatic cancer cells treated with fisetin exhibit increased autophagic cell death and apoptosis. In experimental models, fisetin has been shown to inhibit pancreatic cancer cell proliferation, reduce cell viability, and induce apoptosis, highlighting its therapeutic potential. This dual mechanism enhances the effectiveness of fisetin in reducing tumor growth and improving potential treatment outcomes.
Breast Cancer
Breast cancer, including triple-negative breast cancer, responds to fisetin treatment through inhibition of cell proliferation and induction of apoptosis. Fisetin’s ability to target multiple breast cancer cell lines highlights its versatility and potential in breast cancer therapy.
Gastric and Colorectal Cancer
In gastric cancer cells and human colon cancer cells, fisetin inhibits cellular proliferation and induces cell cycle arrest. This effect is accompanied by modulation of oxidative stress and reactive oxygen species, contributing to cancer cell death and suppression of tumor progression.
Ovarian Cancer
Ovarian cancer is a significant health concern for women worldwide, and new therapeutic strategies are continually being explored to improve outcomes. The effects of fisetin on ovarian cancer cells have shown considerable promise in preclinical studies. Fisetin has been found to induce apoptosis in ovarian cancer cells, effectively triggering programmed cell death through the activation of key cell signaling pathways, including the NF-κB pathway.
In addition to inducing apoptosis, fisetin treatment leads to cell cycle arrest in ovarian cancer cells, halting their progression through the cell cycle and thereby inhibiting cell proliferation. This dual action—inducing apoptosis and causing cell cycle arrest—contributes to the suppression of ovarian cancer cell growth. The ability of fisetin to modulate multiple signaling pathways and inhibit cell proliferation positions it as a promising compound for the treatment of ovarian cancer.
Other Cancers
Fisetin’s anticancer effects extend to bladder cancer cells, lung cancer cells, glioma cancer cells, melanoma cells, ovarian cancer, and liver cancer. Across these various cancer cell lines, fisetin consistently inhibits cell growth, induces apoptosis, and modulates critical signaling pathways, demonstrating broad-spectrum anticancer potential.
In preclinical studies, the Lewis lung carcinoma model in mice has been used to assess the antitumor efficacy and improved drug delivery of fisetin formulations, highlighting their potential for enhanced bioavailability and tumor growth inhibition. Researchers are exploring innovative delivery systems, such as nanoparticles and liposomes, to improve fisetin’s solubility, addressing its poor bioavailability and enhancing its therapeutic potential. Nanocochleates have been shown to improve the bioavailability of fisetin by up to 141 times after sustained release of the drug.
Mechanisms Underlying Fisetin-Induced Cell Death
Fisetin induces multiple forms of programmed cell death, including apoptosis and autophagy. The fisetin-induced apoptosis involves activation of caspases and regulation of gene expression governing cell survival and death. Additionally, fisetin-induced autophagy contributes to cellular stress responses and degradation of damaged organelles, further promoting cancer cell death.
The generation of reactive oxygen species (ROS) following fisetin treatment leads to oxidative stress within cancer cells, triggering apoptosis and inhibiting cell migration. This oxidative stress also influences cell signaling pathways such as NF-κB, further enhancing fisetin’s anticancer effects. Additionally, fisetin reduces the generation of inflammatory cytokines and reactive oxygen species (ROS) in microglial cells, contributing to its anticancer effects.
Fisetin and Cancer Stem Cells
Cancer stem cells represent a unique and challenging subpopulation within tumors, characterized by their ability to self-renew and drive cancer initiation, progression, and recurrence. The effects of fisetin on cancer stem cells have been the subject of growing research interest, as targeting these cells is crucial for achieving long-term cancer control.
Fisetin has demonstrated the ability to inhibit the growth and survival of cancer stem cells by inducing apoptosis through the activation of critical cell signaling pathways, such as the PI3K/AKT/MTOR pathway. This fisetin-induced apoptosis disrupts the self-renewal capacity of cancer stem cells, making them more susceptible to cell death. Furthermore, fisetin has been shown to induce cell cycle arrest in cancer stem cells, further limiting their ability to proliferate and sustain tumor growth.
By targeting both the survival and self-renewal mechanisms of cancer stem cells, fisetin offers a promising approach to overcoming resistance and preventing cancer recurrence. Its effects on cancer cells, including cancer stem cells, highlight its potential as an integral component of future cancer therapies.
Implications for Cancer Therapy and Prevention
The ability of fisetin to inhibit tumor growth, induce cell cycle arrest, and promote cancer cell death presents significant implications for cancer therapy. Its effect on various signaling pathways and selective action on tumor cells over normal cells make fisetin a promising candidate for adjunct cancer treatment.
Furthermore, fisetin’s role in cancer prevention is supported by studies demonstrating its capacity to reduce plasma LDL cholesterol concentration and oxidative stress, factors associated with chronic diseases, including cancer. In rat bladder carcinogenesis models, fisetin treatment has been shown to inhibit tumor progression, suggesting potential preventive benefits.
For more detailed information on fisetin’s anticancer properties, you can visit resources such as the Fisetin Powder: Senolytic Activator for Anti-Aging & Longevity, National Cancer Institute, PubMed Central, and ClinicalTrials.gov.
Conclusion
Fisetin’s multifaceted effect on cancer cells, including its ability to induce apoptosis, autophagy, and cell cycle arrest, positions it as a potent natural compound in the fight against cancer. Its modulation of key signaling pathways such as PI3K/AKT/mTOR and NF-κB further enhances its therapeutic potential across various cancer types, including prostate cancer, pancreatic cancer, breast cancer, and more.
As research continues to uncover the molecular mechanisms behind fisetin’s anticancer effects, its integration into cancer therapy and prevention strategies holds promise for improving outcomes in cancer patients. Hygieia Biotech supports further exploration of fisetin as a natural, effective agent in cancer treatment regimens aimed at inhibiting tumor growth and promoting cancer cell death. Fisetin is also under investigation for its potential therapeutic benefits in cancer treatment, particularly in enhancing physical function in breast cancer patients post-chemotherapy and exploring its role in senolytic therapies. However, fisetin is not an approved treatment for cancer, and more human clinical trials are necessary to confirm its effectiveness and safety. Fisetin has poor bioavailability due to its extreme hydrophobicity.