Curcumin down-regulates the multidrug-resistance mdr1b gene by inhibiting the PI3K/Akt/NFκB pathway
Introduction
Multidrug resistance (MDR) is characterized by cross-resistance to a broad spectrum of structurally and functionally unrelated cytotoxic agents [1]. Development of MDR in tumor cells represents one of the major clinical barriers for the chemotherapy of cancer. It is generally thought that the overexpression of P-glycoprotein (P-gp), a product of the mdr gene family, is a predominant cause of the acquisition of an MDR phenotype. P-gp is an ATP-dependent transmembrane drug transporter that reduces intracellular drug concentrations by pumping drugs out of the cells [2]. In humans, there are two MDR genes: MDR1 and MDR2. MDR1 is involved in the transport of anticancer agents, whereas MDR2 is involved in phospholipid transport. In rodents, there are three mdr genes: mdr1a, mdr1b, and mdr2. The mdr1a and mdr1b genes are closely related to MDR1 and function as multidrug transporters, whereas mdr2 is a phospholipid transporter, similar to MDR2.
Curcumin is a component of the culinary spice turmeric, which is often used in curry powder. Curcumin exerts antioxidant, anti-inflammatory, anti-carcinogenic, and chemopreventive activities on many tumor cells [3]. It has been reported that curcumin inhibits P-gp expression in multidrug-resistant human cancer cells [4], [5]. However, the mechanism underlying the down-regulation of P-gp expression by curcumin has not been elucidated.
Our aim was to evaluate whether curcumin could modulate the mdr1b gene promoter activity. We describe new experimental evidence that curcumin downregulates P-gp expression at the transcriptional level via the phosphatidyinositol 3-kinase (PI3K)/Akt/nuclear factor-κB (NF-κB) signal cascade in the multidrug-resistant mouse leukemia L1210/Adr cell line.
Section snippets
Materials
Curcumin was purchased from Sigma–Aldrich (St. Louis, MO, USA). Rabbit polyclonal P-gp antibody was obtained from Oncogene (San Diego, CA, USA). Antibodies directed against Akt, phospho-Akt (Ser473), GSK-3β, and phospho-GSK-3β (Ser9) were obtained from Cell Signaling Technology (Beverly, MA, USA). Antipoly( ADP-ribose) polymerase (PARP) antibody was obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA).
Cell culture
The L1210 mouse leukemia cell line was obtained from the American Type Culture
Effect of curcumin on P-gp expression in multidrug-resistant L1210/Adr cells
The adriamycin-resistant L1210 subline (L1210/Adr) confers resistance to a variety of conventional anticancer drugs [6]. The MDR of L1210/Adr cells is acquired due to the overexpression of P-gp [6]. To confirm these observations, Western blotting was performed in L1210/Adr cells using an antibody specific for P-gp. As expected, Pgp was highly expressed in L1210/Adr cells, but not in parental L1210 cells, NIH3T3 fibroblasts, or U87MG human glioma cells (Fig. 1A).
To investigate the effects of
Acknowledgements
This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (03-PJ1-PG3-20900-0049) and by Grant 0620400-1 from the National Cancer Center Korea.
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