JAK2 Inhibitor, Fedratinib, Inhibits P-gp Activity and Co-Treatment Induces Cytotoxicity in Antimitotic Drug-Treated P-gp Overexpressing Resistant KBV20C Cancer Cells

by Selleckchem | Jan 17 2024

P-glycoprotein (P-gp) overexpression is one of the major mechanisms of multidrug resistance (MDR). Previously, co-treatment with Janus kinase 2 (JAK2) inhibitors sensitized P-gp-overexpressing drug-resistant cancer cells. In this study, we assessed the cytotoxic effects of JAK2 inhibitor, fedratinib, on drug-resistant KBV20C cancer cells. We found that co-treatment with fedratinib at low doses induced cytotoxicity in KBV20C cells treated with vincristine (VIC). However, fedratinib-induced cytotoxicity was little effect on VIC-treated sensitive KB parent cells, suggesting that these effects are specific to resistant cancer cells. Fluorescence-activated cell sorting (FACS), Western blotting, and annexin V analyses were used to further investigate fedratinib's mechanism of action in VIC-treated KBV20C cells. We found that fedratinib reduced cell viability, increased G2 arrest, and upregulated apoptosis when used as a co-treatment with VIC. G2 phase arrest and apoptosis in VIC-fedratinib-co-treated cells resulted from the upregulation of p21 and the DNA damaging marker pH2AX. Compared with dimethyl sulfoxide (DMSO)-treated cells, fedratinib-treated KBV20C cells showed two-fold higher P-gp-inhibitory activity, indicating that VIC-fedratinib sensitization is dependent on the activity of fedratinib. Similar to VIC, fedratinib co-treatment with other antimitotic drugs (i.e., eribulin, vinorelbine, and vinblastine) showed increased cytotoxicity in KBV20C cells. Furthermore, VIC-fedratinib had similar cytotoxic effects to co-treatment with other JAK2 inhibitors (i.e., VIC-CEP-33779 or VIC-NVP-BSK805) at the same dose; similar cytotoxic mechanisms (i.e., early apoptosis) were observed between treatments, suggesting that co-treatment with JAK2 inhibitors is generally cytotoxic to P-gp-overexpressing resistant cancer cells. Given that fedratinib is FDA-approved, our findings support its application in the co-treatment of P-gp-overexpressing cancer patients showing MDR.

Comments:

This study you've described sounds fascinating! It seems to demonstrate promising results regarding the potential use of fedratinib, a JAK2 inhibitor, in addressing multidrug resistance in cancer cells that overexpress P-glycoprotein (P-gp). The findings suggest that co-administration of fedratinib with certain chemotherapy drugs, like vincristine (VIC), enhances cytotoxicity specifically in drug-resistant cancer cells without significantly affecting sensitive cells.

The mechanism behind this effect appears to involve several pathways. Fedratinib, when used in combination with VIC, induces cell death, G2 phase arrest, and increases apoptosis in the drug-resistant cells. These effects seem to be mediated by upregulating certain markers like p21 and pH2AX, indicating DNA damage and cell cycle arrest. Additionally, the study notes that fedratinib also exhibits P-gp-inhibitory activity, possibly contributing to the increased sensitivity of the drug-resistant cells to VIC.

What's especially promising is that the enhanced cytotoxic effects were not solely limited to VIC but were observed when fedratinib was combined with other antimitotic drugs as well. Moreover, the study suggests that other JAK2 inhibitors also showed similar cytotoxic effects when combined with VIC, indicating a potential class effect among JAK2 inhibitors in sensitizing P-gp-overexpressing resistant cancer cells.

The fact that fedratinib is already FDA-approved could potentially accelerate its application in clinical settings for patients exhibiting multidrug resistance due to P-gp overexpression. This study's findings could pave the way for further clinical trials and research exploring the efficacy of fedratinib-based combination therapies in treating multidrug-resistant cancers.

It's exciting to see how this research could translate into improved treatment strategies for patients facing challenges with multidrug resistance.