Continuous exposure to therapeutic drugs doxorubicin and vincristine reduces drug efficacy through transcriptional and post-transcriptional regulation of P-glycoprotein in follicular lymphoma.

Resistance to drugs used at the onset of follicular lymphoma could develop after continued drug treatment or at the time of recurrence. Therefore, we investigated how the continuous exposure to therapeutic drugs affects P-gp and drug resistance using follicular lymphoma cells. The mRNA expression levels of P-gp in Sci-1 cells treated with Dox or Dox + Vinc were increased. The increase in protein levels was consistent with the behavior of mRNA. The efflux clearance of Rho123 in Sci-1 cells exposed to Dox or Dox + Vinc was significantly increased. In cells continuously exposed to Dox or Dox + Vinc, a significant increase in the IC50 of Dox and an inhibitory effect of Vera on this increase were observed. It has been revealed that therapeutic drugs for follicular lymphoma, such as Dox or Dox + Vinc, increase the expression level of P-gp at the transcriptional level. The transport function of P-gp and drug resistance were enhanced depending on the increase in the amount of P-gp expressed on the membrane. Consequently, our results suggested that continuous exposure to clinical blood levels of Dox + Vinc can significantly affect drug resistance in follicular lymphoma by enhancing P-gp function through transcriptional and post-transcriptional regulation.