Effects of guttiferone k, oblongifolin c and isojacareubin on expression of p-glycoprotein in caco-2 cells

Abstract

Two benzophenones, guttiferone K (GK) and oblongifolin C (OC), and a xanthone, isojacaruebin (ISO), were phytochemicals isolated from the wood of Garcinia schomburgkiana (Thai name: Ma-dan). These three compounds exhibited cytotoxic activity against several cancer cell lines. However, the capability of these compounds to increase chemo-resistance in cancer cells was not reported. The objective of this study was to investigate the effects of these compounds on the oxidative stress-mediated up-regulation of MDR1 mRNA in the Caco-2 cells, and the involvement of MAPK pathway. The cells treated with each of these compounds (50 µM) for 24 h had the amount of MDR1 mRNA increased significantly, as measured by qRT-PCR assay. The up-regulation of MDR1 in this study was related to oxidative stress generated from cellular exposure to these compounds. Addition of n-acetyl cysteine (NAC; a ROS scavenger) in the culture was able to abolish the inductive effect of GK, OC and ISO on MDR1 mRNA level. Moreover, MAPK inhibitors including U0126 (an inhibitor of ERK1/2/MAPK activity) and SB202190 (an inhibitor of p-38/MAPK activity) were able to suppress an increase of MDR1 mRNA levels in the cells treated with benzophenones and xanthone, respectively. These findings were in agreement with the increase of phosphorylated form of either ERK1/2 (p-ERK1/2) or p38 (p-p38) upon treatment of the cells with these three compounds. In addition, OC and ISO, but not GK, increased mRNA of c-JUN/AP-1 level. These results suggested that GK, OC and ISO were able to up-regulate MDR1 mRNA in Caco-2 cells via the activation of oxidative stress-mediated mitogen-activated kinase (MAPK) signaling pathway. Further determination of their inductive effect on P-gp protein level might be pursued.