Isoreserpine Reverses Multidrug Resistance Mediated by ABCB1
DOI:
https://doi.org/10.6000/1929-2279.2015.04.04.7Keywords:
Multidrug resistance, Isoreserpine, ABCB1.Abstract
One of the major obstacles to successful cancer chemotherapy is the development of multidrug resistance (MDR) that is associated with the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 (P-glycoprotein/ MDR1). Currently, the most efficient way to overcome ABCB1-mediated MDR in cancer is by direct inhibition of ABCB1 function. Many drugs with known biological activities have been discovered to inhibit the function of ABCB1 and reverse ABCB1-mediated MDR in cancers. However, clinical trial results suggested that many of these clinically active drugs should not be used as ABCB1 modulators due to direct toxicity or undesirable side effects. In this study, we demonstrated that isoreserpine, an indole alkaloid with relatively low toxicity, can significantly inhibit ABCB1-mediated efflux of calcein-AM, a known substrate of ABCB1, in a dose-dependent manner. Moreover, we showed that at non-toxic concentrations, isoreserpine potently reversed ABCB1-mediated resistance to doxorubicin and colchicine in ABCB1-overexpressing human KB-V-1 epidermal cancer cells. Collectively, our findings revealed thatby inhibiting the transport function of ABCB1, isoreserpine can restore drug sensitivity of ABCB1-overexpressing cells to conventional chemotherapeutic drugs. In conclusion, isoreserpine should be further developed into a promising reversal agent for the treatment of MDR in ABCB1-overexpressing cancers.
References
Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annual Review of Biochemistry 1993; 62: 385-427. http://dx.doi.org/10.1146/annurev.bi.62.070193.002125
Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nature Reviews 2006; 5: 219-34. http://dx.doi.org/10.1038/nrd1984
Dano K. Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells. Biochimica et Biophysica Acta 1973; 323: 466-83. http://dx.doi.org/10.1016/0005-2736(73)90191-0
Shen DW, Cardarelli C, Hwang J, Cornwell M, Richert N, Ishii S, et al. Multiple drug-resistant human KB carcinoma cells independently selected for high-level resistance to colchicine, adriamycin, or vinblastine show changes in expression of specific proteins. J Biol Chem 1986; 261: 7762-70.
Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002; 2: 48-58. http://dx.doi.org/10.1038/nrc706
Hegedus C, Ozvegy-Laczka C, Szakacs G, Sarkadi B. Interaction of ABC multidrug transporters with anticancer protein kinase inhibitors: substrates and/or inhibitors? Curr Cancer Drug Targets 2009; 9: 252-72. http://dx.doi.org/10.2174/156800909788166565
Szakacs G, Varadi A, Ozvegy-Laczka C, Sarkadi B. The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discovery Today 2008; 13: 379-93. http://dx.doi.org/10.1016/j.drudis.2007.12.010
Wu CP, Calcagno AM, Ambudkar SV. Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies. Current Molecular Pharmacology 2008; 1: 93-105. http://dx.doi.org/10.2174/1874467210801020093
Shukla S, Wu CP, Ambudkar SV. Development of inhibitors of ATP-binding cassette drug transporters: present status and challenges. Expert Opin Drug Metab Toxicol 2008; 4: 205-23. http://dx.doi.org/10.1517/17425255.4.2.205
Wu CP, Sim HM, Huang YH, Liu YC, Hsiao SH, Cheng HW, et al. Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells. Biochem Pharmacol 2013; 85: 325-34. http://dx.doi.org/10.1016/j.bcp.2012.11.003
Shen DW, Fojo A, Chin JE, Roninson IB, Richert N, Pastan I, et al. Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. Science 1986; 232: 643-5. http://dx.doi.org/10.1126/science.3457471
Wu CP, Hsiao SH, Sim HM, Luo SY, Tuo WC, Cheng HW, et al. Human ABCB1 (P-glycoprotein) and ABCG2 mediate resistance to BI 2536, a potent and selective inhibitor of Polo-like kinase 1. Biochem Pharmacol 2013; 86: 904-13. http://dx.doi.org/10.1016/j.bcp.2013.08.004
Gribar JJ, Ramachandra M, Hrycyna CA, Dey S, Ambudkar SV. Functional characterization of glycosylation-deficient human P-glycoprotein using a vaccinia virus expression system. J Membr Biol 2000; 173: 203-14. http://dx.doi.org/10.1007/s002320001020
Ishiyama M, Tominaga H, Shiga M, Sasamoto K, Ohkura Y, Ueno K. A combined assay of cell viability and in vitro cytotoxicity with a highly water-soluble tetrazolium salt, neutral red and crystal violet. Biol Pharm Bull 1996; 19: 1518-20. http://dx.doi.org/10.1248/bpb.19.1518
Wu CP, Hsiao SH, Su CY, Luo SY, Li YQ, Huang YH, et al. Human ATP-Binding Cassette transporters ABCB1 and ABCG2 confer resistance to CUDC-101, a multi-acting inhibitor of histone deacetylase, epidermal growth factor receptor and human epidermal growth factor receptor 2. Biochem Pharmacol 2014; 92: 567-76. http://dx.doi.org/10.1016/j.bcp.2014.10.003
Wu CP, Shukla S, Calcagno AM, Hall MD, Gottesman MM, Ambudkar SV. Evidence for dual mode of action of a thiosemicarbazone, NSC73306: a potent substrate of the multidrug resistance linked ABCG2 transporter. Mol Cancer Ther 2007; 6: 3287-96. http://dx.doi.org/10.1158/1535-7163.MCT-07-2005
Lu JC, Chang YT, Wang CT, Lin YC, Lin CK, Wu ZS. Trichostatin A modulates thiazolidinedione-mediated suppression of tumor necrosis factor alpha-induced lipolysis in 3T3-L1 adipocytes. PLoS One 2013; 8: e71517. http://dx.doi.org/10.1371/journal.pone.0071517
Ansbro MR, Shukla S, Ambudkar SV, Yuspa SH, Li L. Screening Compounds with a Novel High-Throughput ABCB1-Mediated Efflux Assay Identifies Drugs with Known Therapeutic Targets at Risk for Multidrug Resistance Interference. PLoS One 2013; 8: e60334. http://dx.doi.org/10.1371/journal.pone.0060334
Deeley RG, Cole SP. Substrate recognition and transport by multidrug resistance protein 1 (ABCC1). FEBS Letters 2006; 580: 1103-11. http://dx.doi.org/10.1016/j.febslet.2005.12.036
Allen JD, van Loevezijn A, Lakhai JM, van der Valk M, van Tellingen O, Reid G, et al. 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 2002; 1: 417-25.
Sun L, Chen W, Qu L, Wu J, Si J. Icaritin reverses multidrug resistance of HepG2/ADR human hepatoma cells via downregulation of MDR1 and Pglycoprotein expression. Molecular Medicine Reports 2013; 8: 1883-7. http://dx.doi.org/10.3892/mmr.2013.1742
Natarajan K, Bhullar J, Shukla S, Burcu M, Chen ZS, Ambudkar SV, et al. The Pim kinase inhibitor SGI-1776 decreases cell surface expression of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and drug transport by Pim-1-dependent and -independent mechanisms. Biochem Pharmacol 2013; 85: 514-24. http://dx.doi.org/10.1016/j.bcp.2012.12.006
Akiyama S, Cornwell MM, Kuwano M, Pastan I, Gottesman MM. Most drugs that reverse multidrug resistance also inhibit photoaffinity labeling of P-glycoprotein by a vinblastine analog. Mol Pharmacol 1988; 33: 144-7.
Beck WT, Cirtain MC, Glover CJ, Felsted RL, Safa AR. Effects of indole alkaloids on multidrug resistance and labeling of P-glycoprotein by a photoaffinity analog of vinblastine. Biochemical and Biophysical Research Communications 1988; 153: 959-66. http://dx.doi.org/10.1016/S0006-291X(88)81321-4
Pearce HL, Safa AR, Bach NJ, Winter MA, Cirtain MC, Beck WT. Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance. Proc Natl Acad Sci USA 1989; 86: 5128-32. http://dx.doi.org/10.1073/pnas.86.13.5128
Wierdl M, Wall A, Morton CL, Sampath J, Danks MK, Schuetz JD, et al. Carboxylesterase-mediated sensitization of human tumor cells to CPT-11 cannot override ABCG2-mediated drug resistance. Mol Pharmacol 2003; 64: 279-88. http://dx.doi.org/10.1124/mol.64.2.279
Bessho Y, Oguri T, Achiwa H, Muramatsu H, Maeda H, Niimi T, et al. Role of ABCG2 as a biomarker for predicting resistance to CPT-11/SN-38 in lung cancer. Cancer Science 2006; 97: 192-8. http://dx.doi.org/10.1111/j.1349-7006.2006.00164.x
Achor RW, Hanson NO, Gifford RW, Jr. Hypertension treated with Rauwolfia serpentina (whole root) and with reserpine; controlled study disclosing occasional severe depression. Journal of the American Medical Association 1955; 159: 841-5. http://dx.doi.org/10.1001/jama.1955.02960260011004