Cordycepin re-sensitizes multidrug resistance cancer cells to chemotherapeutic agents through modulating P-glycoprotein expression and ATPase function

Multidrug resistance (MDR) cancer is one of the major issues in systemic chemotherapy. Development of MDR reversal agents from natural products has been considered as a potential and safe solution. The present study aimed at investigating whether cordycepin, a major constituent in dietary mushrooms, exhibited MDR reversal effect and the mechanisms of kinetic interactions were further explored. Treatment of cordycepin not only modulated the expression of human P-glycoprotein (P-gp), but inhibited P-gp function through stimulating P-gp ATPase activity in cells that stably expressed human P-gp (ABCB1/Flp-InTM-293) and in MDR cancer cells (KB-vin) without influencing cell viability. The molecular docking model demonstrated that cordycepin may interact with P-gp by hydrogen bonds at the nucleotide binding domain. Furthermore, cordycepin significantly re-sensitized MDR cancer cells (KB-vin, HepG2-vin and NCI-H460/MX20) to conventional chemotherapeutic agents, such as paclitaxel and mitoxantrone. These findings suggest a promising combination use of cordycepin with chemotherapeutic agents in cancer treatment.