Abstract 4617: Fisetin, a multi-kinase inhibitor enhances chemotherapeutic sensitivity in head and neck cancer

Abstract Background: The limitations of chemotherapeutic applications are often imposed by dose-related toxicity and the emergence of therapeutic resistance. Fisetin, a naturally occurring flavonoid, has demonstrated anticancer properties in various cancer types. Despite its proven effectiveness against cancer, the molecular target of fisetin remains unknown. Methods: Our study focused on understanding how fisetin and chemotherapy work together to inhibit the growth and survival of human HNC. We conducted in silico, in vitro and in vivo investigations. We employed target prediction, kinase profiling, transcriptome analysis and tumor xenograft to identify the chemosensitivity efficacy and mechanism of fisetin. Results: In-silico target prediction suggested that fisetin might target multiple kinases. Based on this lead, we have screened fisetin for different kinase inhibition activities and found that it inhibits multiple CDKs including CDK1, 2, 4, 5 and 6 at nanomolar concentration. To test its cellular activity, we have selected the head and neck cancer (HNC) model and found that fisetin treatment strongly inhibited cell proliferation and arrested the HNC cells in G1 phase followed by apoptotic cell death. In tumor xenograft experiment, we found that oral fisetin treatment inhibited the FaDu and SAS tumor growth in the athymic mouse model. Transcriptome analysis on FaDu and SAS cell lines indicated that fisetin treatment significantly modulates pathways associated with cell cycle progression and regulation. These pathways include cellular assembly, DNA replication, cell death, and cell morphology. Pretreatment of HNC cells with fisetin improved the effectiveness of chemotherapy drugs including cisplatin, 5-fluorouracil, and docetaxel. Consistent with this, fisetin pre-treated cells showed elevated levels of cellular and mitochondrial ROS followed by the activation of caspases and apoptosis induction when compared with that in control cells after cisplatin, 5-FU, or docetaxel treatment. Conclusion: These results imply that fisetin has the potential to be utilized as a multi-kinase inhibitor in cancer cells. The study revealed that fisetin has a strong potential for increasing the sensitivity of cancer cells to chemotherapy. Citation Format: Dhanir Tailor, Deepali Mishra, Sanjay V. Malhotra, Rana P. Singh. Fisetin, a multi-kinase inhibitor enhances chemotherapeutic sensitivity in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4617.