JAK2 Inhibitor, Fedratinib, Inhibits P-gp Activity and Co-Treatment Induces Cytotoxicity in Antimitotic Drug-Treated P-gp Overexpressing Resistant KBV20C Cancer Cells
P-glycoprotein (P-gp) overexpression is among the major mechanisms of multidrug resistance (MDR). Formerly, co-treatment with Janus kinase 2 (JAK2) inhibitors sensitized P-gp-overexpressing drug-resistant cancer cells. Within this study, we assessed the cytotoxic results of JAK2 inhibitor, fedratinib, on drug-resistant KBV20C cancer cells. We discovered that co-treatment with fedratinib at low doses caused cytotoxicity in KBV20C cells given vincristine (VIC). However, fedratinib-caused cytotoxicity was little impact on VIC-treated sensitive KB parent cells, suggesting these effects are specific to resistant cancer cells. Fluorescence-activated cell sorting (FACS), Western blotting, and annexin V analyses were utilised to help investigate fedratinib’s mechanism of action in VIC-treated KBV20C cells. We discovered that fedratinib reduced cell viability, elevated G2 arrest, and upregulated apoptosis when utilized as a co-treatment with VIC. G2 phase arrest and apoptosis in VIC-fedratinib-co-treated cells resulted in the upregulation of p21 and also the DNA damaging marker pH2AX. In contrast to dimethyl sulfoxide (DMSO)-treated cells, fedratinib-treated KBV20C cells demonstrated two-fold greater P-gp-inhibitory activity, indicating that VIC-fedratinib sensitization relies upon the game of fedratinib. Much like VIC, fedratinib co-treatment along with other antimitotic drugs (i.e., eribulin, vinorelbine, and vinblastine) NVP-BSK805 demonstrated elevated cytotoxicity in KBV20C cells. In addition, VIC-fedratinib had similar cytotoxic effects to co-treatment along with other JAK2 inhibitors (i.e., VIC-CEP-33779 or VIC-NVP-BSK805) in the same dose similar cytotoxic mechanisms (i.e., early apoptosis) were observed between treatments, suggesting that co-treatment with JAK2 inhibitors is usually cytotoxic to P-gp-overexpressing resistant cancer cells. Considering that fedratinib is Food and drug administration-approved, our findings support its application within the co-management of P-gp-overexpressing cancer patients showing MDR.