Down-regulation of intracellular reactive oxygen species attenuates P-glycoprotein-associated chemoresistance in Epstein-Barr virus-positive NK/T-cell lymphoma

Epstein-Barr virus (EBV)-positive extranodal NK/T-cell lymphoma is a rare and highly aggressive disease with a poor prognosis and strong resistance to anti-cancer drugs. Reactive oxygen species (ROS) are closely related to tumorigenesis and P-glycoprotein (P-gp) is highly expressed in various cancers. However, the exact relationship between ROS and P-gp in EBV-positive lymphoma remains unclear. In this study, we demonstrated that EBV latent infection induced intracellular ROS production and increased ROS levels triggered elevated P-gp expression, which resulted in strong resistance to existing anti-cancer drugs in EBV-positive lymphoma cell lines and in patients’ tissue samples. We also verified that regulation of intracellular ROS reduced P-gp expression and function via inhibition of STAT1 phosphorylation. These results indicate that treatment with a ROS scavenger is a potential therapeutic strategy to overcome resistance to anti-cancer drugs by downregulating the expression of P-gp in EBV-positive NK/T-cell lymphoma.