Reverses MDR-1 Mediated Doxorubicin Resistance via in Human Liver Cancer HepG2 Cells.

Objective: The aim of the recent study was to investigate the effects of on reversing Doxorubicin (DOX) resistance, as chemotherapeutic agents through up-regulation of in human liver cancer HepG2 cells.

Materials And Methods: In this experimental study, the drug resistance in liver cancer cells via drug efflux inhibition and enhancing apoptosis by the regulation of and multi-drug resistance/ P-glycoprotein (MDR/P-gp) expression was revealed. Using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, effect of DOX on cell proliferation was evaluated after transfection in HepG2 and HepG2/DOX cells. Activity of P-gp on drug efflux was measured by the Rhodamine 123 (Rho-123) assay. mRNA expression levels were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and flow cytometry was used to measure the apoptotic ratio of HepG2/DOX cells.

Results: overexpression considerably inhibited the HepG2/DOX cells viability (P<0.05). qRT-PCR results revealed that is a pivotal regulator in PI3K/Akt/P-gp axis. Overexpression resulted in up-regulation and ultimately down-regulation of P-gp. This inhibits drug resistance, proliferation and induces apoptosis in HepG2/DOX cells (P<0.05). Whilst, treatment with 10 μM of special inhibitors, including LY294002 (PI3K) or PD098059 (MAPK), increased Rho 123-associated MFI, treatment with 10 μM of SF1670 () almost abolished the effect of overexpression (P<0.05). Finally, we found that was down-regulated in HepG2/DOX cells, and its overexpression led to enhancing apoptosis with re-sensitization of HepG2/DOX cell lines to DOX through PTEN/PI3K/ Akt/MDR1 pathway.

Conclusion: These findings may introduce as a predictive biomarker and a potential treatment target for liver cancer therapy during MDR.