Strategy to enhance efficacy of doxorubicin by curcumin as a potent Pgp inhibitor in gastric cancer

Gastric cancer which usually affects older people is the third leading cancer responsible for cancer related deaths. Chemotherapy used to treat gastric cancer usually fails due to the development of multidrug resistance. The aim of our work is to develop a strategy that overcomes the chemo resistance in gastric cancer cells which enhance the efficacy of doxorubicin by curcumin as a potent PGP inhibitor. In this study we generated a doxo resistant gastric cancer cell line (Doxo-SNU-5) with IC50 22 μM as compared to its wild type with IC50 2.2 μM. The resistance developed was due to overexpression of Pglycoprotein, MRP1 and BCRP confirmed by RT-PCR. Doxo-SNU-5 cells when treated with non-toxic dose of curcumin (PGP inhibitor) in combination with doxorubicin IC50 was reduced up to 5 μM and decreased the cologenetic property. Morphological analysis by DAPI staining showed that the death was due to apoptosis that was further confirmed by annexin V FITC. The biochemical changes of apoptosis was confirmed by increased expression of pro-apoptotic proteins which was due to increase in the expression of CHEK2, BAX, γH2AX and decrease in the expression of anti-apoptotic gene (BCL2) in Doxo-SNU-5 as shown by RT-PCR. These results strongly supports the idea that Curcumin as a Pgp inhibitor enhances the sensitivity of doxorubicin in chemo resistant gastric cancer cell line.