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Cancer Chemotherapy and Pharmacology

Published in:

01-09-2011 | Original Article

Modulatory effects of curcumin on multi-drug resistance-associated protein 5 in pancreatic cancer cells

Authors: Yan Li, Jezrael L. Revalde, Glen Reid, James W Paxton

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2011

Abstract

Purpose

Chemotherapy of pancreatic cancer often fails due to the development of intrinsic and acquired resistance during drug treatment. Recent studies have suggested that MRP5 conferred resistance to first-line drugs 5-fluorouracil and gemcitabine by active efflux of drugs from the cell. Our aim was to evaluate whether curcumin could reverse this multi-drug resistance by inhibition of MRP5-mediated efflux.

Methods

MRP5 protein was detected and localized by immunocytochemistry using a monoclonal antibody in MRP5 over-expressing HEK293 (HEK293/MRP5) cells and two pancreatic cancer cell lines PANC-1 and MiaPaCa-2. The cellular accumulation of a specific MRP5 fluorescent substrate 2′,7′-Bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) into these cells was measured by flow cytometry and the cell proliferation determined by a 72-h CyQuant assay.

Results

The cellular accumulation of BCECF in HEK293/MRP5 cells and in PANC-1 and MiaPaCa-2 cells was significantly increased by curcumin in a concentration-dependent manner. Curcumin and a MRP5 inhibitor MK571 had no apparent effects on cellular accumulation of BCECF in parental HEK293 cells. In the proliferation assays, curcumin caused a concentration-dependant increase in the sensitivity to the cytotoxic drug 5-fluorouracil in HEK293/MRP5 cells, PANC-1 and MiaPaCa-2 pancreatic cancer cells, but not in parental HEK293 cells.

Conclusions

Our results suggest that curcumin is an inhibitor of MRP5 and may be useful in the reversal of multi-drug resistance in pancreatic cancer chemotherapy.

Sultana A, Ghaneh P, Cunningham D, Starling N, Neoptolemos JP, Smith CT (2008) Gemcitabine based combination chemotherapy in advanced pancreatic cancer-indirect comparison. BMC Cancer 8:192. doi:1471-2407-8-192[pii]10.1186/1471-2407-8-192 PubMedCrossRef

Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, Harper PG, Dunn J, Tudur-Smith C, West J, Falk S, Crellin A, Adab F, Thompson J, Leonard P, Ostrowski J, Eatock M, Scheithauer W, Herrmann R, Neoptolemos JP (2009) Phase iii randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 27(33):5513–5518. doi:JCO.2009.24.2446[pii]10.1200/JCO.2009.24.2446 PubMedCrossRef

Borst P, Elferink RO (2002) Mammalian abc transporters in health and disease. Annu Rev Biochem 71:537–592. doi:10.1146/annurev.biochem.71.102301.093055102301.093055[pii] PubMedCrossRef

Konig J, Hartel M, Nies AT, Martignoni ME, Guo J, Buchler MW, Friess H, Keppler D (2005) Expression and localization of human multidrug resistance protein (abcc) family members in pancreatic carcinoma. Int J Cancer 115(3):359–367. doi:10.1002/ijc.20831 PubMedCrossRef

Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5(3):219–234. doi:nrd1984[pii]10.1038/nrd1984 PubMedCrossRef

Hagmann W, Jesnowski R, Faissner R, Guo C, Lohr JM (2009) Atp-binding cassette c transporters in human pancreatic carcinoma cell lines. Upregulation in 5-fluorouracil-resistant cells. Pancreatology 9(1-2):136–144. doi:000178884[pii]10.1159/000178884 PubMedCrossRef

Hagmann W, Jesnowski R, Matthias Löhr J (2010) Interdependence of gemcitabine treatment, transporter expression and resistance in human pancreatic carcinoma cells. Neoplasma 12(9):740–747. doi:10.1593/neo.10576

Oguri T, Achiwa H, Sato S, Bessho Y, Takano Y, Miyazaki M, Muramatsu H, Maeda H, Niimi T, Ueda R (2006) The determinants of sensitivity and acquired resistance to gemcitabine differ in non-small cell lung cancer: a role of abcc5 in gemcitabine sensitivity. Mol Cancer Ther 5(7):1800–1806. doi:5/7/1800[pii]10.1158/1535-7163.MCT-06-0025 PubMedCrossRef

Shukla S, Wu CP, Ambudkar SV (2008) Development of inhibitors of atp-binding cassette drug transporters: present status and challenges. Expert Opin Drug Metab Toxicol 4(2):205–223. doi:10.1517/17425255.4.2.205 PubMedCrossRef

10.

Chearwae W, Shukla S, Limtrakul P, Ambudkar SV (2006) Modulation of the function of the multidrug resistance-linked atp-binding cassette transporter abcg2 by the cancer chemopreventive agent curcumin. Mol Cancer Ther 5(8):1995–2006. doi:5/8/1995[pii]10.1158/1535-7163.MCT-06-0087 PubMedCrossRef

11.

Zhang SZ, Yang XN, Morris ME (2004) Flavonoids are inhibitors of breast cancer resistance protein (abcg2)-mediated transport. Mol Pharmacol 65(5):1208–1216PubMedCrossRef

12.

Wu CP, Calcagno AM, Hladky SB, Ambudkar SV, Barrand MA (2005) Modulatory effects of plant phenols on human multidrug-resistance proteins 1, 4 and 5 (abcc1, 4 and 5). FEBS J 272(18):4725–4740. doi:EJB4888[pii]10.1111/j.1742-4658.2005.04888.x PubMedCrossRef

13.

Limtrakul P, Chearwae W, Shukla S, Phisalphong C, Ambudkar SV (2007) 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(1–2):85–95. doi:10.1007/s11010-006-9302-8 PubMedCrossRef

14.

Anuchapreeda S, Leechanachai P, Smith MM, Ambudkar SV, Limtrakul PN (2002) Modulation of p-glycoprotein expression and function by curcumin in multidrug-resistant human kb cells. Biochem Pharmacol 64(4):573–582. doi:S0006295202012248[pii] PubMedCrossRef

15.

Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB (2007) Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappab-regulated gene products. Cancer Res 67(8):3853–3861. doi:67/8/3853[pii]10.1158/0008-5472.CAN-06-4257 PubMedCrossRef

16.

Patel BB, Sengupta R, Qazi S, Vachhani H, Yu Y, Rishi AK, Majumdar AP (2008) Curcumin enhances the effects of 5-fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating egfr and igf-1r. Int J Cancer 122(2):267–273. doi:10.1002/ijc.23097 PubMedCrossRef

17.

Bisht S, Mizuma M, Feldmann G, Ottenhof NA, Hong SM, Pramanik D, Chenna V, Karikari C, Sharma R, Goggins MG, Rudek MA, Ravi R, Maitra A (2010) Systemic administration of polymeric nanoparticle-encapsulated curcumin (nanocurc) blocks tumor growth and metastases in preclinical models of pancreatic cancer. Mol Cancer Ther 9(8):2255–2264. doi:1535-7163.MCT-10-0172

18.

Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, Ng CS, Badmaev V, Kurzrock R (2008) Phase ii trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 14(14):4491–4499. doi:14/14/4491[pii]10.1158/1078-0432.CCR-08-0024 PubMedCrossRef

19.

Pratt S, Shepard RL, Kandasamy RA, Johnston PA, Perry W 3rd, Dantzig AH (2005) The multidrug resistance protein 5 (abcc5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol Cancer Ther 4(5):855–863. doi:4/5/855[pii]10.1158/1535-7163.MCT-04-0291 PubMedCrossRef

20.

Hirohashi T, Terasaki T, Shigetoshi M, Sugiyama Y (1997) In vivo and in vitro evidence for nonrestricted transport of 2′, 7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein tetraacetoxymethyl ester at the blood-brain barrier. J Pharmacol Exp Ther 280(2):813–819PubMed

21.

McAleer MA, Breen MA, White NL, Matthews N (1999) Pabc11 (also known as moat-c and mrp5), a member of the abc family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells. J Bio Chem 274(33):23541–23548CrossRef

22.

Saif MW, Choma A, Salamone SJ, Chu E (2009) Pharmacokinetically guided dose adjustment of 5-fluorouracil: a rational approach to improving therapeutic outcomes. J Natl Cancer Inst 101(22):1543–1552. doi:10.1093/jnci/djp328 PubMedCrossRef

23.

GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group PX, Oba K, Burzykowski T, Michiels S, Ohashi Y, Pignon JP, Rougier P, Sakamoto J, Sargent D, Sasako M, Van Cutsem E, Buyse M (2010) Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis. JAMA 303(17):1729–1737. doi:10.1001/jama.2010.534 PubMedCrossRef

24.

Wijnholds J, Mol CAAM, van Deemter L, de Haas M, Scheffer GL, Baas F, Beijnen JH, Scheper RJ, Hatse S, De Clercq E, Balzarini J, Borst P (2000) Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci U S A 97(13):7476–7481PubMedCrossRef

25.

Wielinga PR, Reid G, Challa EE, van der Heijden I, van Deemter L, de Haas M, Mol C, Kuil AJ, Groeneveld E, Schuetz JD, Brouwer C, De Abreu RA, Wijnholds J, Beijnen JH, Borst P (2002) Thiopurine metabolism and identification of the thiopurine metabolites transported by mrp4 and mrp5 overexpressed in human embryonic kidney cells. Mol Pharmacol 62(6):1321–1331PubMedCrossRef

26.

Wielinga P, Hooijberg JH, Gunnarsdottir S, Kathmann I, Reid G, Zelcer N, van der Born K, de Haas M, van der Heijden I, Kaspers G, Wijnholds J, Jansen G, Peters G, Borst P (2005) The human multidrug resistance protein mrp5 transports folates and can mediate cellular resistance against antifolates. Cancer Res 65(10):4425–4430. doi:65/10/4425[pii]10.1158/0008-5472.CAN-04-2810 PubMedCrossRef

27.

Reid G, Wielinga P, Zelcer N, De Haas M, Van Deemter L, Wijnholds J, Balzarini J, Borst P (2003) Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins mrp4 and mrp5. Mol Pharmacol 63(5):1094–1103PubMedCrossRef

28.

Solazzo M, Fantappie O, D’Amico M, Sassoli C, Tani A, Cipriani G, Bogani C, Formigli L, Mazzanti R (2009) Mitochondrial expression and functional activity of breast cancer resistance protein in different multiple drug-resistant cell lines. Cancer Res 69(18):7235–7242. doi:0008-5472.CAN-08-4315[pii]10.1158/0008-5472.CAN-08-4315 PubMedCrossRef

29.

Jaruga E, Sokal A, Chrul S, Bartosz G (1998) Apoptosis-independent alterations in membrane dynamics induced by curcumin. Exp Cell Res 245(2):303–312. doi:S0014-4827(98)94225-2[pii]10.1006/excr.1998.4225 PubMedCrossRef

30.

Guo Y, Kotova E, Chen ZS, Lee K, Hopper-Borge E, Belinsky MG, Kruh GD (2003) Mrp8, atp-binding cassette c11 (abcc11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2′, 3′-dideoxycytidine and 9′-(2′-phosphonylmethoxyethyl)adenine. J Bio Chem 278(32):29509–29514. doi:10.1074/jbc.M304059200M304059200[pii] CrossRef

31.

Zhao L, Pan Y, Gang Y, Wang H, Jin H, Tie J, Xia L, Zhang Y, He L, Yao L, Qiao T, Li T, Liu Z, Fan D (2009) Identification of gas1 as an epirubicin resistance-related gene in human gastric cancer cells with a partially randomized small interfering rna library. J Biol Chem 284(39):26273–26285. doi:M109.028068[pii]10.1074/jbc.M109.028068 PubMedCrossRef

32.

Bharti AC, Donato N, Singh S, Aggarwal BB (2003) Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa b and ikappabalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 101(3):1053–1062. doi:10.1182/blood-2002-05-13202002-05-1320[pii] PubMedCrossRef

33.

Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ (1999) The nuclear factor-kappa b rela transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 5(1):119–127PubMed

34.

Kuo MT, Liu Z, Wei Y, Lin-Lee YC, Tatebe S, Mills GB, Unate H (2002) Induction of human mdr1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate nf-kappab signaling. Oncogene 21(13):1945–1954PubMedCrossRef

35.

Sims-Mourtada J, Izzo JG, Ajani J, Chao KS (2007) Sonic hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene 26(38):5674–5679. doi:1210356[pii]10.1038/sj.onc.1210356 PubMedCrossRef

36.

Labbozzetta M, Notarbartolo M, Poma P, Maurici A, Inguglia L, Marchetti P, Rizzi M, Baruchello R, Simoni D, D’Alessandro N (2009) Curcumin as a possible lead compound against hormone-independent, multidrug-resistant breast cancer. Ann N Y Acad Sci 1155:278–283. doi:NYAS03699[pii]10.1111/j.1749-6632.2009.03699.x PubMedCrossRef

37.

Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007) Bioavailability of curcumin: Problems and promises. Mol Pharm 4(6):807–818. doi:10.1021/mp700113r PubMedCrossRef

38.

Bisht S, Feldmann G, Soni S, Ravi R, Karikar C, Maitra A (2007) Polymeric nanoparticle-encapsulated curcumin (“Nanocurcumin”): a novel strategy for human cancer therapy. J Nanobiotechnology 5:3. doi:1477-3155-5-3[pii]10.1186/1477-3155-5-3 PubMedCrossRef

39.

Chen C, Johnston TD, Jeon H, Gedaly R, McHugh PP, Burke TG, Ranjan D (2009) An in vitro study of liposomal curcumin: Stability, toxicity and biological activity in human lymphocytes and epstein-barr virus-transformed human b-cells. Int J Pharm 366(1–2):133–139. doi:S0378-5173(08)00620-0[pii]10.1016/j.ijpharm.2008.09.009 PubMedCrossRef

40.

Cui J, Yu B, Zhao Y, Zhu W, Li H, Lou H, Zhai G (2009) Enhancement of oral absorption of curcumin by self-microemulsifying drug delivery systems. Int J Pharm 371(1–2):148–155. doi:S0378-5173(08)00824-7[pii]10.1016/j.ijpharm.2008.12.009 PubMedCrossRef

41.

Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Olah A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Buchler MW, For the European Study Group for Pancreatic C (2010) Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 304(10):1073–1081. doi:10.1001/jama.2010.1275 PubMedCrossRef

42.

Fang J, Nakamura H, Maeda H (2010) The epr effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev. doi:S0169-409X(10)00090-6 [pii] 10.1016/j.addr.2010.04.009

Title: Modulatory effects of curcumin on multi-drug resistance-associated protein 5 in pancreatic cancer cells
Authors: Yan Li
Jezrael L. Revalde
Glen Reid
James W Paxton
Publication date: 01-09-2011
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1515-6

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