Reversal effect of PI3-K inhibitor LY294002 on P-glycoprotein-mediated multidrug resistance of human leukemia cell line K562/DNR and gastric cancer cell line SGC7901/ADR.

BACKGROUND AND OBJECTIVE

Phosphatidylinositol-3-kinase/protein kinase B (PI3-K/Akt) signaling pathway plays an important role in cell survival. This study was to explore the reversal effect of PI3-K inhibitor LY294002 on p-glycoprotein (P-gp)-mediated multidrug resistance in human leukemia cell line K562/DNR and gastric cancer cell line SGC7901/ADR.

METHODS

The cells were divided into simple drug-treated groups and LY294002 pretreated groups: the former groups received treatment of daunorubicin (DNR), adriamycin (ADR), vincristine (VCR) and etoposide (VP-16), respectively; the latter groups received pretreatment of LY294002 before drug treatment. Trypan blue dye exclusion method and MTT assay were used to detect the drug sensitivity of K562/DNR and SGC7901/ADR cells, and the effect of LY294002 on the drug resistance. The expression of P-gp and phosphorylated Akt (p-Akt) in K562/DNR, SGC7901/ADR and their parental cell lines K562 and SGC7901 was detected by Western blot. Intracellular drug accumulation was measured by flow cytometry (FCM).

RESULTS

LY294002 pretreatment significantly decreased the 50% inhibition concentration (IC(50)) of DNR, ADR, VCR and VP-16 for K562/DNR cells, with reverse efficiencies of 72.4%, 64.9%, 60.4% and 52.8%. In SGC7901/ADR cells, the similar result was obtained with a reverse efficiency of 31.0%. LY294002 pretreatment partially inhibited the expression of p-Akt and P-gp, and promoted the intracellular accumulation of DNR and ADR in K562/DNR and SGC7901/ADR cells, respectively.

CONCLUSION

LY294002 could partially reverse multidrug resistance in K562/DNR and SGC7901/ADR cells in vitro via inhibiting PI3-K/Akt pathway.