Multidrug resistance-associated protein 4 is a determinant of arsenite resistance

Yuan,Bo; Yoshino,Yuta; Fukushima,Hisayo; Markova,Svetlana; Takagi,Norio; Toyoda,Hiroo; Kroetz,Deanna  L.

doi:10.3892/or.2015.4343

Multidrug resistance-associated protein 4 is a determinant of arsenite resistance

Authors:
- Bo Yuan
- Yuta Yoshino
- Hisayo Fukushima
- Svetlana Markova
- Norio Takagi
- Hiroo Toyoda
- Deanna L. Kroetz
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Affiliations: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94143, USA, Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan, Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
Published online on: October 22, 2015 https://doi.org/10.3892/or.2015.4343
Pages: 147-154

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Abstract

Although arsenic trioxide (arsenite, AsIII) has shown a remarkable efficacy in the treatment of acute promyelocytic leukemia patients, multidrug resistance is still a major concern for its clinical use. Multidrug resistance-associated protein 4 (MRP4), which belongs to the ATP-binding cassette (ABC) superfamily of transporters, is localized to the basolateral membrane of hepatocytes and the apical membrane of renal proximal tubule cells. Due to its characteristic localization, MRP4 is proposed as a candidate in the elimination of arsenic and may contribute to resistance to AsIII. To test this hypothesis, stable HEK293 cells overexpressing MRP4 or MRP2 were used to establish the role of these two transporters in AsIII resistance. The IC50 values of AsIII in MRP4 cells were approximately 6-fold higher than those in MRP2 cells, supporting an important role for MRP4 in resistance to AsIII. The capacity of MRP4 to confer resistance to AsIII was further confirmed by a dramatic decrease in the IC50 values with the addition of MK571, an MRP4 inhibitor, and cyclosporine A, a well-known broad-spectrum inhibitor of ABC transporters. Surprisingly, the sensitivity of the MRP2 cells to AsIII was similar to that of the parent cells, although insufficient formation of glutathione and/or Se conjugated arsenic compounds in the MRP2 cells might limit transport. Given that MRP4 is a major contributor to arsenic resistance in vitro, further investigation into the correlation between MRP4 expression and treatment outcome of leukemia patients treated with arsenic-based regimens is warranted.

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1	Yuan B, Yoshino Y, Kaise T and Toyoda H: Application of arsenic trioxide therapy for patients with leukemia. Biological Chemistry of Arsenic, Antimony and Bismuth. Sun H: John Wiley and Sons, Ltd; Chichester: pp. 263–292. 2011
2	Cohen MH, Hirschfeld S, Flamm Honig S, Ibrahim A, Johnson JR, O'Leary JJ, White RM, Williams GA and Pazdur R: Drug approval summaries: Arsenic trioxide, tamoxifen citrate, anastrazole, paclitaxel, bexarotene. Oncologist. 6:4–11. 2001. View Article : Google Scholar : PubMed/NCBI
3	Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang W, Sun GL, Yang KQ, et al: Use of arsenic trioxide (As₂O₃) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 89:3354–3360. 1997.PubMed/NCBI
4	Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, Corso D, DeBlasio A, Gabrilove J, Scheinberg DA, et al: Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 339:1341–1348. 1998. View Article : Google Scholar : PubMed/NCBI
5	Fujisawa S, Ohno R, Shigeno K, Sahara N, Nakamura S, Naito K, Kobayashi M, Shinjo K, Takeshita A, Suzuki Y, et al: Pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia treated with arsenic trioxide. Cancer Chemother Pharmacol. 59:485–493. 2007. View Article : Google Scholar
6	Kiguchi T, Yoshino Y, Yuan B, Yoshizawa S, Kitahara T, Akahane D, Gotoh M, Kaise T, Toyoda H and Ohyashiki K: Speciation of arsenic trioxide penetrates into cerebrospinal fluid in patients with acute promyelocytic leukemia. Leuk Res. 34:403–405. 2010. View Article : Google Scholar
7	Yoshino Y, Yuan B, Miyashita SI, Iriyama N, Horikoshi A, Shikino O, Toyoda H and Kaise T: Speciation of arsenic trioxide metabolites in blood cells and plasma of a patient with acute promyelocytic leukemia. Anal Bioanal Chem. 393:689–697. 2009. View Article : Google Scholar
8	Iriyama N, Yoshino Y, Yuan B, Horikoshi A, Hirabayashi Y, Hatta Y, Toyoda H and Takeuchi J: Speciation of arsenic trioxide metabolites in peripheral blood and bone marrow from an acute promyelocytic leukemia patient. J Hematol Oncol. 5:12012. View Article : Google Scholar : PubMed/NCBI
9	Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, Cai X, Han ZG, Ni JH, Shi GY, Jia PM, et al: Use of arsenic trioxide (As₂O₃) in the treatment of acute promyelocytic leukemia (APL): I. As₂O₃ exerts dose-dependent dual effects on APL cells. Blood. 89:3345–3353. 1997.PubMed/NCBI
10	Morjani H and Madoulet C: Immunosuppressors as multidrug resistance reversal agents. Methods Mol Biol. 596:433–446. 2010. View Article : Google Scholar
11	Lee TC, Ho IC, Lu WJ and Huang JD: Enhanced expression of multidrug resistance-associated protein 2 and reduced expression of aquaglyceroporin 3 in an arsenic-resistant human cell line. J Biol Chem. 281:18401–18407. 2006. View Article : Google Scholar : PubMed/NCBI
12	Leslie EM, Haimeur A and Waalkes MP: Arsenic transport by the human multidrug resistance protein 1 (MRP1/ABCC1). Evidence that a tri-glutathione conjugate is required. J Biol Chem. 279:32700–32708. 2004. View Article : Google Scholar : PubMed/NCBI
13	Bhattacharjee H, Carbrey J, Rosen BP and Mukhopadhyay R: Drug uptake and pharmacological modulation of drug sensitivity in leukemia by AQP9. Biochem Biophys Res Commun. 322:836–841. 2004. View Article : Google Scholar : PubMed/NCBI
14	Yoshino Y, Yuan B, Kaise T, Takeichi M, Tanaka S, Hirano T, Kroetz DL and Toyoda H: Contribution of aquaporin 9 and multidrug resistance-associated protein 2 to differential sensitivity to arsenite between primary cultured chorion and amnion cells prepared from human fetal membranes. Toxicol Appl Pharmacol. 257:198–208. 2011. View Article : Google Scholar : PubMed/NCBI
15	Iriyama N, Yuan B, Yoshino Y, Hatta Y, Horikoshi A, Aizawa S, Takeuchi J and Toyoda H: Aquaporin 9, a promising predictor for the cytocidal effects of arsenic trioxide in acute promyelocytic leukemia cell lines and primary blasts. Oncol Rep. 29:2362–2368. 2013.PubMed/NCBI
16	Yuan B, Ohyama K, Bessho T and Toyoda H: Contribution of inducible nitric oxide synthase and cyclooxygenase-2 to apoptosis induction in smooth chorion trophoblast cells of human fetal membrane tissues. Biochem Biophys Res Commun. 341:822–827. 2006. View Article : Google Scholar : PubMed/NCBI
17	Yuan B, Ohyama K, Bessho T, Uchide N and Toyoda H: Imbalance between ROS production and elimination results in apoptosis induction in primary smooth chorion trophoblast cells prepared from human fetal membrane tissues. Life Sci. 82:623–630. 2008. View Article : Google Scholar : PubMed/NCBI
18	Yuan B, Ohyama K, Takeichi M and Toyoda H: Direct contribution of inducible nitric oxide synthase expression to apoptosis induction in primary smooth chorion trophoblast cells of human fetal membrane tissues. Int J Biochem Cell Biol. 41:1062–1069. 2009. View Article : Google Scholar
19	Abla N, Chinn LW, Nakamura T, Liu L, Huang CC, Johns SJ, Kawamoto M, Stryke D, Taylor TR, Ferrin TE, et al: The human multidrug resistance protein 4 (MRP4, ABCC4): Functional analysis of a highly polymorphic gene. J Pharmacol Exp Ther. 325:859–868. 2008. View Article : Google Scholar : PubMed/NCBI
20	Kelly L, Fukushima H, Karchin R, Gow JM, Chinn LW, Pieper U, Segal MR, Kroetz DL and Sali A: Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains. Protein Sci. 19:2110–2121. 2010. View Article : Google Scholar : PubMed/NCBI
21	Russel FG, Koenderink JB and Masereeuw R: Multidrug resistance protein 4 (MRP4/ABCC4): A versatile efflux transporter for drugs and signalling molecules. Trends Pharmacol Sci. 29:200–207. 2008. View Article : Google Scholar : PubMed/NCBI
22	Chen ZS, Lee K, Walther S, Raftogianis RB, Kuwano M, Zeng H and Kruh GD: Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer Res. 62:3144–3150. 2002.PubMed/NCBI
23	Tian Q, Zhang J, Chan SY, Tan TM, Duan W, Huang M, Zhu YZ, Chan E, Yu Q, Nie YQ, et al: Topotecan is a substrate for multidrug resistance associated protein 4. Curr Drug Metab. 7:105–118. 2006. View Article : Google Scholar : PubMed/NCBI
24	Tian Q, Zhang J, Tan TM, Chan E, Duan W, Chan SY, Boelsterli UA, Ho PC, Yang H, Bian JS, et al: Human multidrug resistance associated protein 4 confers resistance to camptothecins. Pharm Res. 22:1837–1853. 2005. View Article : Google Scholar : PubMed/NCBI
25	Copsel S, Bruzzone A, May M, Beyrath J, Wargon V, Cany J, Russel FG, Shayo C and Davio C: Multidrug resistance protein 4/ATP binding cassette transporter 4: A new potential therapeutic target for acute myeloid leukemia. Oncotarget. 5:9308–9321. 2014. View Article : Google Scholar : PubMed/NCBI
26	Oevermann L, Scheitz J, Starke K, Köck K, Kiefer T, Dölken G, Niessen J, Greinacher A, Siegmund W, Zygmunt M, et al: Hematopoietic stem cell differentiation affects expression and function of MRP4 (ABCC4), a transport protein for signaling molecules and drugs. Int J Cancer. 124:2303–2311. 2009. View Article : Google Scholar : PubMed/NCBI
27	Banerjee M, Carew MW, Roggenbeck BA, Whitlock BD, Naranmandura H, Le XC and Leslie EM: A novel pathway for arsenic elimination: Human multidrug resistance protein 4 (MRP4/ABCC4) mediates cellular export of dimethylarsinic acid (DMAV) and the diglutathione conjugate of monomethylarsonous acid (MMAIII). Mol Pharmacol. 86:168–179. 2014. View Article : Google Scholar : PubMed/NCBI
28	Lee K, Klein-Szanto AJ and Kruh GD: Analysis of the MRP4 drug resistance profile in transfected NIH3T3 cells. J Natl Cancer Inst. 92:1934–1940. 2000. View Article : Google Scholar : PubMed/NCBI
29	Lee G and Piquette-Miller M: Influence of IL-6 on MDR and MRP-mediated multidrug resistance in human hepatoma cells. Can J Physiol Pharmacol. 79:876–884. 2001. View Article : Google Scholar : PubMed/NCBI
30	Schuetz JD, Connelly MC, Sun D, Paibir SG, Flynn PM, Srinivas RV, Kumar A and Fridland A: MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med. 5:1048–1051. 1999. View Article : Google Scholar : PubMed/NCBI
31	Kikuchi H, Yuan B, Yuhara E, Imai M, Furutani R, Fukushima S, Hazama S, Hirobe C, Ohyama K, Takagi N, et al: Involvement of histone H3 phosphorylation via the activation of p38 MAPK pathway and intracellular redox status in cytotoxicity of HL-60 cells induced by Vitex agnus-castus fruit extract. Int J Oncol. 45:843–852. 2014.PubMed/NCBI
32	Carew MW and Leslie EM: Selenium-dependent and -independent transport of arsenic by the human multidrug resistance protein 2 (MRP2/ABCC2): Implications for the mutual detoxification of arsenic and selenium. Carcinogenesis. 31:1450–1455. 2010. View Article : Google Scholar : PubMed/NCBI
33	Kala SV, Neely MW, Kala G, Prater CI, Atwood DW, Rice JS and Lieberman MW: The MRP2/cMOAT transporter and arsenic-glutathione complex formation are required for biliary excretion of arsenic. J Biol Chem. 275:33404–33408. 2000. View Article : Google Scholar : PubMed/NCBI
34	Copsel S, Garcia C, Diez F, Vermeulem M, Baldi A, Bianciotti LG, Russel FG, Shayo C and Davio C: Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation. J Biol Chem. 286:6979–6988. 2011. View Article : Google Scholar : PubMed/NCBI
35	Zhao Q, Tao J, Zhu Q, Jia PM, Dou AX, Li X, Cheng F, Waxman S, Chen GQ, Chen SJ, et al: Rapid induction of cAMP/PKA pathway during retinoic acid-induced acute promyelocytic leukemia cell differentiation. Leukemia. 18:285–292. 2004. View Article : Google Scholar
36	Zhu Q, Zhang JW, Zhu HQ, Shen YL, Flexor M, Jia PM, Yu Y, Cai X, Waxman S, Lanotte M, et al: Synergic effects of arsenic trioxide and cAMP during acute promyelocytic leukemia cell maturation subtends a novel signaling cross-talk. Blood. 99:1014–1022. 2002.PubMed/NCBI