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.