Skip to main content

Advertisement

SpringerLink
Log in

Curcumin Inhibits the Activity of ABCG2/BCRP1, a Multidrug Resistance-Linked ABC Drug Transporter in Mice

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To evaluate the in vivo efficacy of curcumin as an inhibitor of the multidrug-resistance-linked ATP Binding Cassette (ABC) drug transporter, ABCG2.

Methods

Photoaffinity labeling with [125I]-iodoarylazidoprazosin was used to characterize the interaction of sulfasalazine, a substrate of the mouse ABCG2, with human ABCG2. In addition, the inhibitory effect of curcumin on ABCG2 was evaluated in brain capillaries from rats. Furthermore, the effect of curcumin on absorption of orally administered sulfasalazine in wild-type and abcg2 −/− mice was also determined.

Results

Sulfasalazine interacted at the drug-substrate site(s) of human ABCG2. Curcumin inhibited ABCG2 activity at nanomolar concentrations at the rat blood-brain barrier in the ex vivo assay. Based on studies in wild type and abcg2 −/− mice, we observed that oral curcumin increased C max and relative bioavailability of sulfasalazine by selectively inhibiting ABCG2 function.

Conclusions

This study validates our previous in vitro results with human ABCG2 (Chearwae et al., Mol. Cancer Ther. 5:1995–2006, 2006) and provides the first in vivo evidence for the inhibition by curcumin of ABCG2-mediated efflux of sulfasalazine in mice. Based on these studies, we propose that non-toxic concentrations of curcumin may be used to enhance drug exposure when the rate-limiting step of drug absorption and/or tissue distribution is impacted by ABCG2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ABC:

ATP binding cassette

AUC:

area under concentration-time curve

BBB:

blood–brain barrier

IAAP:

iodoarylazidoprazosin

MDR:

multidrug resistance

P-gp:

P-glycoprotein

SASP:

sulfasalazine

REFERENCES

  1. S. Shishodia, M. M. Chaturvedi, and B. B. Aggarwal. Role of curcumin in cancer therapy. Curr. Probl. Cancer. 31:243–305 (2007) doi:10.1016/j.currproblcancer.2007.04.001.

    Article  PubMed  Google Scholar 

  2. B. B. Aggarwal, and S. Shishodia. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharmacol. 71:1397–1421 (2006) doi:10.1016/j.bcp.2006.02.009.

    Article  PubMed  CAS  Google Scholar 

  3. H. Choi, Y.-S. Chun, S.-W. Kim, M.-S. Kim, and J.-W. Park. Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: a mechanism of tumor growth inhibition. Mol. Pharmacol. 70:1664–1671 (2006) doi:10.1124/mol.106.025817.

    Article  PubMed  CAS  Google Scholar 

  4. A. Duvoix, R. Blasius, S. Delhalle, M. Schnekenburger, F. Morceau, E. Henry, M. Dicato, and M. Diederich. Chemopreventive and therapeutic effects of curcumin. Cancer Lett. 223:181–190 (2005) doi:10.1016/j.canlet.2004.09.041.

    Article  PubMed  CAS  Google Scholar 

  5. B. B. Aggarwal, A. Kumar, and A. C. Bharti. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 23:363–398 (2003).

    PubMed  CAS  Google Scholar 

  6. B. B. Aggarwal, S. Shishodia, Y. Takada, S. Banerjee, R. A. Newman, C. E. Bueso-Ramos, and J. E. Price. Curcumin suppresses the paclitaxel-induced nuclear factor-kappa B pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin. Cancer Res. 11:7490–7498 (2005) doi:10.1158/1078-0432.CCR-05-1192.

    Article  PubMed  CAS  Google Scholar 

  7. S. Aggarwal, H. Ichikawa, Y. Takada, S. K. Sandur, S. Shishodia, and B. B. Aggarwal. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol. Pharmacol. 69:195–206 (2006).

    PubMed  CAS  Google Scholar 

  8. S. V. Ambudkar, C. Kimchi-Sarfaty, Z. E. Sauna, and M. M. Gottesman. P-glycoprotein: from genomics to mechanism. Oncogene. 22:7468–7485 (2003) doi:10.1038/sj.onc.1206948.

    Article  PubMed  CAS  Google Scholar 

  9. G. Szakacs, J. K. Paterson, J. A. Ludwig, C. Booth-Genthe, and M. M. Gottesman. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov. 5:219–234 (2006) doi:10.1038/nrd1984.

    Article  PubMed  CAS  Google Scholar 

  10. S. Velamakanni, S. Wei, T. Janvilisri, and H. van Veen. ABCG transporters: structure, substrate specificities and physiological roles. JBioenerg. Biomembr. 39:465–471 (2007) doi:10.1007/s10863-007-9122-x.

    Article  CAS  Google Scholar 

  11. W. Chearwae, S. Anuchapreeda, K. Nandigama, S. V. Ambudkar, and P. Limtrakul. Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from Turmeric powder. Biochem. Pharmacol. 68:2043–2052 (2004) doi:10.1016/j.bcp.2004.07.009.

    Article  PubMed  CAS  Google Scholar 

  12. W. Chearwae, C. P. Wu, H. Y. Chu, T. R. Lee, S. V. Ambudkar, and P. Limtrakul. Curcuminoids purified from turmeric powder modulate the function of human multidrug resistance protein 1 (ABCC1). Cancer Chemother. Pharmacol. 57:376–388 (2005) doi:10.1007/s00280-005-0052-1.

    Article  PubMed  Google Scholar 

  13. W. Chearwae, S. Shukla, P. Limtrakul, and S. V. Ambudkar. Modulation of the function of the multidrug resistance-linked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin. Mol. Cancer Ther. 5:1995–2006 (2006) doi:10.1158/1535-7163.MCT-06-0087.

    Article  PubMed  CAS  Google Scholar 

  14. P. Limtrakul, W. Chearwae, S. Shukla, C. Phisalphong, and S. Ambudkar. Modulation of function of three ABC drug transporters, P-glycoprotein (ABCB1), mitoxantrone resistance protein (ABCG2) and multidrug resistance protein 1 (ABCC1) by tetrahydrocurcumin, a major metabolite of curcumin. Mol. Cell. Biochem. 296:85–95 (2007) doi:10.1007/s11010-006-9302-8.

    Article  PubMed  CAS  Google Scholar 

  15. H. Zaher, A. A. Khan, J. Palandra, T. G. Brayman, L. Yu, and J. A. Ware. Breast cancer resistance protein (Bcrp/abcg2) is a major determinant of sulfasalazine absorption and elimination in the mouse. Mol. Pharm. 3:55–61 (2006) doi:10.1021/mp050113v.

    Article  PubMed  CAS  Google Scholar 

  16. R. W. Robey, W. Y. Medina-Perez, K. Nishiyama, T. Lahusen, K. Miyake, T. Litman, A. M. Senderowicz, D. D. Ross, and S. E. Bates. Overexpression of the ATP-binding cassette half-transporter, ABCG2 (Mxr/BCrp/ABCP1), in flavopiridol-resistant human breast cancer cells. Clin. Cancer Res. 7:145–152 (2001).

    PubMed  CAS  Google Scholar 

  17. R. W. Robey, Y. Honjo, A. van de Laar, K. Miyake, J. T. Regis, T. Litman, and S. E. Bates. A functional assay for detection of the mitoxantrone resistance protein, MXR (ABCG2). Biochim. Biophys. Acta. 1512:171–182 (2001) doi:10.1016/S0005-2736(01)00308-X.

    Article  PubMed  CAS  Google Scholar 

  18. S. V. Ambudkar. Drug-stimulatable ATPase activity in crude membranes of human MDR1- transfected mammalian cells. Methods Enzymol. 292:504–514 (1998) doi:10.1016/S0076-6879(98)92039-0.

    Article  PubMed  CAS  Google Scholar 

  19. S. Shukla, R. W. Robey, S. E. Bates, and S. V. Ambudkar. The calcium channel blockers, 1,4-dihydropyridines, are substrates of the multidrug resistance-linked ABC drug transporter, ABCG2. Biochemistry. 45:8940–8951 (2006) doi:10.1021/bi060552f.

    Article  PubMed  CAS  Google Scholar 

  20. Z. E. Sauna, X. H. Peng, K. Nandigama, S. Tekle, and S. V. Ambudkar. The molecular basis of the action of disulfiram as a modulator of the multidrug resistance-linked ATP binding cassette transporters MDR1 (ABCB1) and MRP1 (ABCC1). Mol. Pharmacol. 65:675–684 (2004) doi:10.1124/mol.65.3.675.

    Article  PubMed  CAS  Google Scholar 

  21. B. Bauer, A. M. Hartz, and D. S. Miller. Tumor necrosis factor alpha and endothelin-1 increase P-glycoprotein expression and transport activity at the blood-brain barrier. Mol. Pharmacol. 71:667–675 (2007) doi:10.1124/mol.106.029512.

    Article  PubMed  CAS  Google Scholar 

  22. B. Bauer, X. Yang, A. M. Hartz, E. R. Olson, R. Zhao, J. C. Kalvass, G. M. Pollack, and D. S. Miller. In vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation. Mol. Pharmacol. 70:1212–1219 (2006) doi:10.1124/mol.106.023796.

    Article  PubMed  CAS  Google Scholar 

  23. B. Bauer, A. M. Hartz, G. Fricker, and D. S. Miller. Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood-brain barrier. Mol. Pharmacol. 66:413–419 (2004).

    PubMed  CAS  Google Scholar 

  24. A. M. Hartz, B. Bauer, M. L. Block, J. S. Hong, and D. S. Miller. Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood–brain barrier. Faseb. J. 22:2723–2733 (2008).

    Article  PubMed  CAS  Google Scholar 

  25. A. M. Hartz, B. Bauer, G. Fricker, and D. S. Miller. Rapid modulation of P-glycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-alpha and lipopolysaccharide. Mol. Pharmacol. 69:462–470 (2006) doi:10.1124/mol.105.017954.

    Article  PubMed  CAS  Google Scholar 

  26. B. Bauer, A. M. Hartz, A. Pekcec, K. Toellner, D. S. Miller, and H. Potschka. Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling. Mol. Pharmacol. 73:1444–1453 (2008) doi:10.1124/mol.107.041210.

    Article  PubMed  CAS  Google Scholar 

  27. T. Eisenblatter, and H. J. Galla. A new multidrug resistance protein at the blood–brain barrier. Biochem. Biophys. Res. Commun. 293:1273–1278 (2002) doi:10.1016/S0006-291X(02)00376-5.

    Article  PubMed  Google Scholar 

  28. W. Zhang, J. Mojsilovic-Petrovic, M. F. Andrade, H. Zhang, M. Ball, and D. B. Stanimirovic. The expression and functional characterization of ABCG2 in brain endothelial cells and vessels. Faseb. J. 17:2085–2087 (2003).

    PubMed  Google Scholar 

  29. R. A. Sharma, A. J. Gescher, and W. P. Steward. Curcumin: the story so far. Eur. J. Cancer. 41:1955–1968 (2005) doi:10.1016/j.ejca.2005.05.009.

    Article  PubMed  CAS  Google Scholar 

  30. Y. Yamasaki, I. Ieiri, H. Kusuhara, T. Sasaki, M. Kimura, H. Tabuchi, Y. Ando, S. Irie, J. A. Ware, Y. Nakai, S. Higuchi, and Y. Sugiyama. Pharmacogenetic characterization of sulfasalazine disposition based on NAT2 and ABCG2 (BCRP) gene polymorphisms in humans. Clin. Pharmacol. Ther. 84:95–103 (2008) doi:10.1038/sj.clpt.6100459.

    Article  PubMed  CAS  Google Scholar 

  31. B. L. Urquhart, J. A. Ware, R. G. Tirona, R. H. Ho, B. F. Leake, U. I. Schwarz, H. Zaher, J. Palandra, J. C. Gregor, G. K. Dresser, and R. B. Kim. Breast cancer resistance protein (ABCG2) and drug disposition: intestinal expression, polymorphisms and sulfasalazine as an in vivo probe. Pharmacogenet. Genomics. 18:439–448 (2008) doi:10.1097/FPC.0b013e3282f974dc.

    Article  PubMed  CAS  Google Scholar 

  32. D. R. Umbenhauer, G. R. Lankas, T. R. Pippert, L. D. Wise, M. E. Cartwright, S. J. Hall, and C. M. Beare. Identification of a P-glycoprotein-deficient subpopulation in the CF-1 mouse strain using a restriction fragment length polymorphism. Toxicol. Appl. Pharmacol. 146:88–94 (1997) doi:10.1006/taap.1997.8225.

    Article  PubMed  CAS  Google Scholar 

  33. J. W. Jonker, M. Buitelaar, E. Wagenaar, M. A. Van Der Valk, G. L. Scheffer, R. J. Scheper, T. Plosch, F. Kuipers, R. P. Elferink, H. Rosing, J. H. Beijnen, and A. H. Schinkel. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc. Natl. Acad. Sci. U. S. A. 99:15649–15654 (2002) doi:10.1073/pnas.202607599.

    Article  PubMed  CAS  Google Scholar 

  34. L. M. S. Chan, S. Lowes, and B. H. Hirst. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur. J. Pharmaceut. Sci. 21:25–51 (2004) doi:10.1016/j.ejps.2003.07.003.

    Article  CAS  Google Scholar 

  35. J. W. Jonker, J. W. Smit, R. F. Brinkhuis, M. Maliepaard, J. H. Beijnen, J. H. Schellens, and A. H. Schinkel. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J. Natl. Cancer. Inst. 92:1651–1656 (2000) doi:10.1093/jnci/92.20.1651.

    Article  PubMed  CAS  Google Scholar 

  36. C. M. Kruijtzer, J. H. Beijnen, and J. H. Schellens. Improvement of oral drug treatment by temporary inhibition of drug transporters and/or cytochrome P450 in the gastrointestinal tract and liver: an overview. Oncologist. 7:516–530 (2002) doi:10.1634/theoncologist.7-6-516.

    Article  PubMed  CAS  Google Scholar 

  37. C. M. Kruijtzer, J. H. Beijnen, H. Rosing, W. W. ten Bokkel Huinink, M. Schot, R. C. Jewell, E. M. Paul, and J. H. Schellens. Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J. Clin. Oncol. 20:2943–2950 (2002) doi:10.1200/JCO.2002.12.116.

    Article  PubMed  CAS  Google Scholar 

  38. D. S. Miller, B. Bauer, and A. M. S. Hartz. Modulation of P-glycoprotein at the blood–brain barrier: opportunities to improve central nervous system pharmacotherapy. Pharmacol. Rev. 60:196–209 (2008) doi:10.1124pr.107.07109.

    Article  PubMed  Google Scholar 

  39. T. H. Marczylo, R. D. Verschoyle, D. N. Cooke, P. Morazzoni, W. P. Steward, and A. J. Gescher. Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine. Cancer Chemother. Pharmacol. 60:171–177 (2007) doi:10.1007/s00280-006-0355-x.

    Article  PubMed  CAS  Google Scholar 

  40. N. Dhillon, B. B. Aggarwal, R. A. Newman, R. A. Wolff, A. B. Kunnumakkara, J. L. Abbruzzese, C. S. Ng, V. Badmaev, and R. Kurzrock. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin. Cancer Res. 14:4491–4499 (2008) doi:10.1158/1078-0432.CCR-08-0024.

    Article  PubMed  CAS  Google Scholar 

  41. P. Anand, A. B. Kunnumakkara, R. A. Newman, and B. B. Aggarwal. Bioavailability of curcumin: problems and promises. Mol. Pharm. 4:807–818 (2007) doi:10.1021/mp700113r.

    Article  PubMed  CAS  Google Scholar 

  42. S. Shukla, C. P. Wu, and S. V. Ambudkar. Development of inhibitors of ATP-binding cassette drug transporters: present status and challenges. Expert Opin. Drug Metab. Toxicol. 4:205–223 (2008) doi:10.1517/17425255.4.2.205.

    Article  PubMed  CAS  Google Scholar 

  43. J. D. Allen, A. van Loevezijn, J. M. Lakhai, M. van der Valk, O. van Tellingen, G. Reid, J. H. Schellens, G. J. Koomen, and A. H. Schinkel. Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. Mol. Cancer Ther. 1:417–425 (2002).

    PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGEMENTS

This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We thank Dr. Krishnamachary Nandigama for providing ABCG2-expressing Hi-five insect cell crude membranes and George Leiman for editorial assistance. The authors wish to acknowledge the contribution of Joe Palandra of Pfizer Global Research and Development for his assistance in determination of SASP bioanalysis and for the input of Lisa Bernstein, Non-clinical Biostatistics, Genentech, Inc.

Author information

Author notes

  1. Hani Zaher

    Present address: Drug Discovery Support, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut, 06877, USA

  2. Joseph A. Ware

    Present address: Genentech Inc., 1-DNA Way, South San Francisco, California, 94080, USA

Authors and Affiliations

  1. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, 20892-4256, USA

    Suneet Shukla & Suresh V. Ambudkar

  2. Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Ann Arbor, Michigan, 48105, USA

    Hani Zaher & Joseph A. Ware

  3. Department of Biochemistry and Molecular Biochemistry, Medical School, University of Minnesota, Duluth, Minnesota, 55812, USA

    Anika Hartz

  4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota, 55812, USA

    Björn Bauer

Authors
  1. Suneet Shukla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hani Zaher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anika Hartz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Björn Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joseph A. Ware
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Suresh V. Ambudkar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suresh V. Ambudkar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shukla, S., Zaher, H., Hartz, A. et al. Curcumin Inhibits the Activity of ABCG2/BCRP1, a Multidrug Resistance-Linked ABC Drug Transporter in Mice. Pharm Res 26, 480–487 (2009). https://doi.org/10.1007/s11095-008-9735-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-008-9735-8

KEY WORDS

Search

Navigation