Chemotherapy is often restricted by dose-related toxicity and development of therapeutic resistance. Fisetin, a natural flavonoid found in various fruits and vegetables has shown anticancer and radiosensitizing effect in lung and prostate cancer. We investigated the mechanisms of Fisetin-induced inhibition of growth and survival of human HNC cells in combination with chemotherapy. We found that a pretreatment of Fisetin (1-10 μM) enhanced the effect of cisplatin, 5-fluorouracil (FU) and docetaxel, in colony formation of HNC cells under hypoxic condition (1% oxygen). The pretreatment enhanced the chemotherapy-induced apoptosis by cisplatin, 5-FU and docetaxel. Consistent with this, Fisetin pretreated cells showed elevated level of cellular and mitochondrial ROS followed by the expression of cleaved caspases-3 and -7 and poly(ADP-ribose)polymerase compared with that in control cells after cisplatin, 5-FU, or docetaxel treatment. This drug also induces the mitochondrial membrane depolarization in pretreated cells. Tagging HNC cells with mito-GFP and mito-RFP showed an elevation in the frequency mictochondial exchange in chemo treated HNC cells under hypoxic condition. Pre-treatment with Fisetin followed by chemo treatment reduces the rate of mitochondrial exchange in HNC cells. Under hypoxic condition, HNC cells show up to 36% resistance as compared to normoxic condition. But, Fisetin enhances the efficacy of chemo drugs and synergize their effect up to 43%. Overall, our data suggest that Fisetin treatment inhibits the HNC cells and sensitize them for chemotherapy under hypoxic condition.

Fisetin sensitizes the hypoxia induced chemotherapy resistance in head and neck cancer

2019 Fall National Meeting

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