?-Tocotrienol reverses multidrug resistance of breast cancer cells through the regulation of the ?-Tocotrienol-NF-?B-P-gp axis

The problem of multidrug resistance (MDR) presents a major obstacle in the chemotherapy of cancer. The MDR phenotype is often linked to the overexpression of ATP-binding cassette (ABC) transporters, that pumps out and decreased intracellular drug accumulation. ?-Tocotrienol, an unsaturated tocopherol belonging to the vitamin E family, has been shown to reverse the MDR of MCF-7/Adr cell. To reveal the role of ?-tocotrienol-NF-?B-P-gp axis in the reversal process, the expression level of mdr1/P-gp was determined by real-time PCR and western blot, while NF-?B activity was detected by immunofluorescence and NF-?B transcriptional activity reporter assay. Besides, mdr1 promoter activity and P-gp transport capacity were measured with the effect of ?-tocotrienol and NF-?B agonist/antagonist. Results showed that ?-tocotrienol effectively inhibited the expression levels of mdr1 mRNA and P-gp protein. It is demonstrated that ?-tocotrienol also suppressed mdr1 promoter activity and the efflux activity of P-gp. In addition, the activation of NF-?B signaling pathway and the transcriptional activity of NF-?B were both reduced by ?-tocotrienol. Evidences also showed that the NF-?B pathway is really involved in the regulation of the expression and function of mdr1/P-gp. Taken together, we confirmed that ?-tocotrienol reversed the MDR of MCF-7/Adr through the signaling pathway of NF-?B and P-gp.