Fisetin Deters Cell Proliferation, Induces Apoptosis, Alleviates Oxidative Stress and Inflammation in Human Cancer Cells, HeLa

Abstract

Background: Fisetin, a flavonol profusely found in vegetables and fruits, exhibited a myriad of properties in preclinical studies to impede cancer growth. Purpose: This study was proposed to delineate molecular mechanisms through analysing the modulated expression of various molecular targets in HeLa cells involved in proliferation, apoptosis and inflammation. Methods: MTT assay, flow cytometry, nuclear morphology, DNA fragmentation and Annexin–Pi were performed to evaluate the anti-cancer potential of fisetin. Furthermore, qPCR and proteome profiler were performed to analyse the expression of variety of gene related to cell death, cell proliferation, oxidative stress and inflammation and cancer pathways. Results: Fisetin demonstrated apoptotic inducing ability in HeLa cells, which was quite evident through nuclear morphology, DNA ladder pattern, decreased TMRE fluorescent intensity, cell cycle arrest at G2/M and increased early and late apoptosis. Furthermore, fisetin treatment modulated pro-apoptotic genes such as APAF1, Bad, Bax, Bid and BIK at both transcript and protein levels and anti-apoptotic gene Bcl-2, BIRC8, MCL-1, XIAP/BIRC4, Livin/BIRC7, clap-2/BIRC3, etc. at protein levels to mitigate cell proliferation and induce apoptosis. Interestingly, the aforementioned alterations consequently led to an elevated level of Caspase-3, Caspase-8 and Caspase-9, which was found to be consistent with the transcript and protein level expression. Moreover, fisetin downregulated the expression of AKT and MAPK pathways to avert proliferation and enhance apoptosis of cancer cells. Fisetin treatment also improves oxidative stress and alleviates inflammation by regulating JAK-STAT/NF-kB pathways. Conclusion: Together, these studies established that fisetin deters human cervical cancer cell proliferation, enhances apoptosis and ameliorates inflammation through regulating various signalling pathways that may be used as a therapeutic regime for better cancer management.

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

“…TGF proteins bind to cell surface receptors, initiating a signaling cascade. We also have incomplete information on the potential of FIS in relation to JAK/STAT [90], sonic hedgehog [132] and NOTCH [133] signaling in various tumors.…”

Mitochondrial Aging and Senolytic Natural Products with Protective Potential

“…Moreover, FIS significantly reduced ROS generation induced in mouse brains by D-galactose (a senescence accelerator), along with neuroinflammation-related pathways and pro-apoptotic markers [147]. Furthermore, FIS is considered an inducer of apoptosis, has a protective effect on the skin and the extracellular matrix, and increases the synthesis of collagen and the availability of glutathione, the main intracellular antioxidant in the human body [148,149]. FIS can protect LDL from oxidation and modulates SIRT-2, supporting cell repair after radical damage [150].…”

Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions

“…In human studies, patients with idiopathic pulmonary fibrosis, a senescence associated disease, improved 6-minute walk distance, walking speed, chair rise ability and short physical performance battery after 9 doses of oral DQ over 3 weeks [ 24 ]. Fisetin is another flavonoid compound that has gained recognition for its anti-proliferative, anti-inflammatory, and anti-metastatic properties [ 15 , 25 ]. Fisetin has the potential to reduce senescence markers in multiple tissues in murine and human subjects [ 12 , 26 ].…”