Curcuminoids purified from turmeric powder modulate the function of human multidrug resistance protein 1 (ABCC1)

Abstract

Multidrug resistance is a major cause of chemotherapy failure in cancer patients. One of the resistance mechanisms is the overexpression of drug efflux pumps such as P-glycoprotein and multidrug resistance protein 1 (MRP1, (ABCC1)). In this study, curcumin mixture and three major curcuminoids purified from turmeric (curcumin I, II, and III) were tested for their ability to modulate the function of MRP1 using HEK293 cells stably transfected with MRP1-pcDNA3.1 and pcDNA3.1 vector alone. The IC(50) of curcuminoids in these cell lines ranged from 14.5-39.3 microM. Upon treating the cells with etoposide in the presence of 10 microM curcuminoids, the sensitivity of etoposide was increased by several folds only in MRP1 expressing and not in pcDNA3.1-HEK 293 cells. Western blot analysis showed that the total cellular level of MRP1 protein level was not affected by treatment with 10 microM curcuminoids for three days. The modulatory effect of curcuminoids on MRP1 function was confirmed by the inhibition of efflux of two fluorescent substrates, calcein-AM and fluo4-AM. Although all the three curcuminoids increased the accumulation of fluorescent substrates in a concentration-dependent manner, curcumin I was the most effective inhibitor. In addition, curcuminoids did not affect 8-azido[alpha-(32)P]ATP binding, however they did stimulate the basal ATPase activity and inhibited the quercetin-stimulated ATP hydrolysis of MRP1 indicating that these bioflavonoids interact most likely at the substrate-binding site(s). In summary, these results demonstrate that curcuminoids effectively inhibit MRP1-mediated transport and among curcuminoids, curcumin I, a major constituent of curcumin mixture, is the best modulator.

Biodegradable micelles enhance the antiglioma activity of curcumin in vitro and in vivo

“…Previous studies demonstrated that Cur can significantly inhibit the proliferation of glioma cells by downregulating multidrug resistance proteins that cause the efflux of many chemotherapeutic agents. 28,29 However, its clinical application is severely restricted due to its low water solubility.…”

Modulation of the function of the multidrug resistance–linked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin

“…We have shown previously that curcuminoids are inhibitors of the ABC transporters, ABCB1 (25,26) and ABCC1 (27), which are known to play a major role in the development of MDR in cancer cells. In this study, purified curcuminoids were tested for their interaction with ABCG2.…”

Solid lipid nanoparticles with TPGS and Brij 78: A co-delivery vehicle of curcumin and piperine for reversing P-glycoprotein-mediated multidrug resistance in vitro

“…NF-κB regulates the expression of genes involved in the suppression of the apoptotic response, and is responsible for tumor cell survival (6). Additionally, Cur is also known to downregulate the intracellular levels of three major ABC drug transporters, P-gp, MDR-associated protein 1 (MRP1) and ABCG2, which are important in MDR (7)(8)(9). In spite of these various promising therapeutic applications of Cur, its therapeutic efficacy is limited due to its markedly poor water solubility, and consequently, remarkably low systemic concentrations are achieved when Cur is consumed orally (4).…”