Multidrug-resistance reversing activity of the local Citrus fruits in Jeju Island, Korea

We examined whether extracts from 14 local citrus spp. on Jeju Island (Korea) contained chemosensitizing activity that would increase the cytotoxic effect of vincristine(VCR) in drug-resistant cancer cells. We report that methanol extracts from fruits and flowers of some species had a chemosensitizing effect that reversed P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). Using drug-sensitive AML-2/WT and drug-resistant AML-2/D100 in the absence of VCR in human acute myelogenous leukemia cells we found that fruit or flower extracts alone generally had low cytotoxicity $(IC_{50}>200\;{\mu}g/ml)$. In studies examining the effect of extracts on 120 ng/ml VCR cytotoxicity in drug-resistant AML-2/D100 cells, we found that immature fruit extracts had greater chemosensitizing activity than either extracts from mature fruit or flower. Of the 14 species examined, the immature fruit extract from Inchangkyool (Citrus ichangiensis) showed the hishest chemosensitizing index(CI) valus. Immature fruit extracts of Hongkyool(C. tachibana), Byungkyool(C. platymamma), Cheongkyool(C. nippokoreana) and Jinkyool (C. sunki) also strongly potentiated VCR cytotoxicity in AML-2/D100 cells. The chemosensitizing effect of peel extracts was 2-10-fold that of whole fruit extracts from Hongkyool (C. tachibana), Byungkyool (C. platymamma) and Inchangkyool (C. inchangiensis). The CI values for flower extracts were higher than those for mature fruit extracts, but lower than those for immature fruit extracts. These results indicate that immature citrus fruits contain compounds that do not exert their activity solely through cytotoxicity. In particular, Incahngkyool (C. inchangiensis), Byungkyool(C.platymamma), Cheongkyool(C. nippokoreana) and Hongkyool (C. tahibana) may be useful sources of chemosensitizing compounds.