Cancer Letters

Cancer Letters

Volume 259, Issue 1, 18 January 2008, Pages 111-118
Cancer Letters

Curcumin down-regulates the multidrug-resistance mdr1b gene by inhibiting the PI3K/Akt/NFκB pathway

https://doi.org/10.1016/j.canlet.2007.10.003Get rights and content

Abstract

Curcumin, a constituent of turmeric, has anti-inflammatory, anti-carcinogenic, and chemopreventive effects in several animal tumor models. The expression of P-glycoprotein (P-gp), encoded by the mdr gene, is often associated with multidrug resistance (MDR) to unrelated chemotherapeutic drugs in cancer cells. Here, we demonstrate that curcumin down-regulates P-gp expression in multidrug-resistant L1210/Adr cells. Transfection with a series of 5′-deleted constructs of the mdr1b gene promoter indicated that a proximal region between −205 and +42 of the sequence was responsible for the suppression of promoter activity by curcumin. This response might be associated with the inhibition of the phosphatidyinositol 3-kinase (PI3K)/Akt/nuclear factor-κB (NF-κB) signaling pathway by curcumin. Moreover, curcumin reversed the MDR of the L1210/Adr cells. Thus, curcumin can contribute to the reversal of the MDR phenotype, probably due to the suppression of P-gp expression via the inhibition of the PI3K/Akt/NF-κB signaling 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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