P-gp upregulation may be blocked by natural curcuminoids, a novel class of chemoresistance-preventing agent

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Abstract
Once multidrug resistance (MDR) occurs in cancer cells, it is very difficult to reverse since overexpression of P-glycoprotein (P-gp) is accompanied by altered expression of numerous other activated target genes. Previously, we reported that curcumin pretreatment would be an ideal method to prevent acquired drug resistance induced by adriamycin, administered prior to the development of MDR. To further confirm the previous results, we examined the potency of 3 forms of curcuminoids present in turmeric as potent preventers of acquired drug resistance. K562 cells were pretreated with or without curcuminoids for 24 h and co-incubated with adriamycin. P-gp and mdr1 mRNA levels were analyzed separately by flow cytometry and quantitative real-time RT-PCR. In addition, we performed an MTT assay to determine the adriamycin-induced cytotoxicity with or without pretreatment with curcuminoids. Short- and long-term exposure of native K562 cells to adriamycin led to upregulation of P-gp and formation of acquired drug resistance. However, after pretreatment with curcuminoids, the above processes were significantly inhibited. The MTT assay examined the enhanced effect of curcuminoids on adriamycin‑induced cytotoxicity. Results from western blotting showed that curcuminoids could inhibit the adriamycin-induced increase of NF-κB nuclear translocation and activation. Finally, under the long-term exposure model, we proved that curcumin was capable of blocking the occurrence of MDR in the cell line throughout the 56-day culture period. This study reveals that curcuminoids have the potency to block the upregulation of P-gp and its mRNA induced by short- and long-term exposure to adriamycin. Curcuminoids may be a novel class of potent chemoresistance-preventing agent with high safety and the potential for widespread clinical use.

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