Augmented sensitivity to methotrexate by curcumin induced overexpression of folate receptor in KG-1 cells

Abstract

Folate receptors are targets of various strategies aimed at efficient delivery of anti-cancer drugs. Folate receptors also play a role in the uptake of antifolate drugs which are used for therapeutic intervention in leukemia. Therefore, it is important to identify compounds which regulate expression of folate receptors in leukemic cells. The present study examined if curcumin could modulate the uptake and cytotoxicity of the antifolate drug methotrexate, in KG-1 leukemic cells. This is the first report to show that curcumin (10-50μM) causes a significant, dose-dependent, 2-3 fold increase in uptake of radiolabelled folic acid and methotrexate into KG-1 cells both at 24h and 48h of treatment. Interestingly, pre-treatment of KG-1 leukemic cells with curcumin (10μM and 25μM) also caused a statistically significant enhancement in the cytotoxicity of methotrexate. We performed Real Time Quantitative RT-PCR to confirm the upregulation of FRβ mRNA in curcumin treated cells. Immunocytochemistry and Western blotting showed that curcumin caused increased expression of folate receptor βin KG-1 cells. Our data show that the mechanism of curcumin action involves up-regulation of folate receptor β mRNA and protein in KG-1 cells. Therefore, combination of non-toxic concentrations of curcumin and methotrexate, may be a viable strategy for therapeutic intervention for leukemias using afolate receptor-targeted drug delivery system.