Alkoxylated fisetin derivatives - the new potential drugs against head and neck cancers

Head and neck squamous cell carcinoma (HNSCC) is a therapeutically challenging cancer what underscoring the need for new chemical agents that selectively induce programmed cell death. Fisetin, a naturally occurring flavonoid, exhibits promising anticancer activity but displays limited proapoptotic efficacy and selectivity. Here, we examined whether alkoxylated modification of fisetin enhances its ability to induce apoptosis in HNSCC cells. Fisetin derivatives bearing four-carbon substituents were synthesized and evaluated in multiple HNSCC cell lines. Two derivatives, MKT218 and MKT257, markedly reduced HNSCC cell viability at low micromolar concentrations with low toxicity towards normal human fibroblasts. Notably, the observed cytotoxicity was not associated with activation of a canonical DNA damage response, as neither {gamma}H2AX accumulation nor p53 activation was detected. Furthermore, PARP1 cleavage and live-cell imaging combined with annexin V/EthD-III staining revealed a significantly higher proportion of apoptotic cells. The effect was stronger following treatment with MKT218 and MKT257 compared with fisetin. Time-lapse microscopy further demonstrated that fisetin derivatives, particularly MKT218, promote mitosis-associated apoptosis, in contrast to the predominantly cytostatic effect of fisetin. Moreover, in silico docking suggested that MKT218 exerts its pro-apoptotic activity through a multi-target interaction profile involving key regulators of cell survival and apoptosis rather than a single dominant target. To sum up, our findings suggest that alkoxylated fisetin derivatives may be constituted as new non-genotoxic inducers of apoptosis in HNSCC cells.