Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids

In this study, natural curcuminoids, pure curcumin, demethoxycurcumin and bisdemethoxycurcumin, isolated from turmeric (Curcuma longa Linn), were compared for their potential ability to modulate the human MDR-1 gene expression in multidrug resistant human cervical carcinoma cell line, KB-V1 by Western blot analysis and RT-PCR.Western blot analysis and RT-PCR showed that all the three curcuminoids inhibited MDR-1 gene expression, and bisdemethoxycurcumin produced maximum effect. In additional studies we found that commercial grade curcuminoid (approximately 77% curcumin, 17% demethoxycurcumin and 3% bisdemthoxycurcumin) decreased MDR-1 gene expression in a dose dependent manner and had about the same potent inhibitory effect on MDR-1 gene expression as our natural curcuminoid mixtures.These results indicate that bisdemethoxycurcumin is the most active of the curcuminoids present in turmeric for modulation of MDR-1 gene. Treatment of drug resistant KB-V1 cells with curcumin increased their sensitivity to vinblastine, which was consistent with a decreased MDR-1 gene product, a P-glycoprotein, on the cell plasma membrane. Although many drugs that prevent the P-glycoprotein function have been reported, this report describes the inhibition of MDR-1 expression by a phytochemical. The modulation of MDR-1 expression may be an attractive target for new chemosensitizing agents.The human MDR-1 gene encoding for MDR transporter (Pgp-170) belongs to ATP-binding cassette (ABC) transporter superfamily. The MDR-1 overexpression has been reported in many tumors and in vitro selected drug-resistant cell lines [1-4]. Uptake and/or efflux of isotope-labelled drugs or rhodamine123 are frequently used for functional assay of Pgp-170 in tumor cells. Several classes of MDR modulators that inhibit Pgp-mediated efflux have been identified. It has been found that the accumulation of chemotherapy agents in tumor cells with overexpressed Pgp-170 was significantly reduced as compared to the MDR a