Concurrent treatment of flavonol with chemotherapeutics potentiates or counteracts the therapeutic implications in cervical cancer cells

BACKGROUND: The negative impact of chemotherapeutic-based monotherapy against cancer necessitates the use of chemotherapeutic drugs in combination with chemopreventive agents which are well-tolerated and safe. The multipronged approach may activate multiple pathways to exhibit a more potent anticarcinogenic effect at lower doses. These combinations may act in therapeutic synergy. This research was designed to study the interactions of two phytochemicals (fisetin and kaempferol) with one another and with chemotherapeutic drugs (topotecan and cisplatin) in HeLa cells. METHODS: Cell viability and colony formation assay, scratch-wound, invasion, and DNA ladder assays were conducted. Further, qPCR was performed to evaluate the gene expression. RESULTS: Simultaneous administration of sub-lethal doses of fisetin/kaempferol with cisplatin, and fisetin with topotecan enhanced the cytotoxicity and apoptosis-inducing properties as these synergistic combinations (Combination Index [CI] value <1) promote cell death, apoptosis and mitigates migration of HeLa cells. Apoptosis-inducing and antimigratory properties were well explained by increasing Bax (Bcl-2 associated X-protein), TIMP1 (tissue inhibitor of metalloproteinases), TIMP2, caspase-8, 9, and 3 expressions whereas Matrix metalloprotein (MMP) 2 and MMP 9 were found to be downregulated. Interestingly, co-treatment of kaempferol with topotecan and fisetin elicited an antagonistic effect on cell viability (CI>1). The antagonizing combination such as K2T2 and K2F2 neither show any significant change in colony formation, migration and DNA fragmentation assay nor altered the nuclear morphology compared to the control cells. However, the individual doses of fisetin and kaempferol have exhibited potent anticancer properties in HeLa cells. CONCLUSIONS: This study demonstrates that 2 or more drugs can act antagonistically or synergistically demanding elucidation of possible mechanistic interactions for better therapeutic outcomes.