P-Glycoprotein 170; Its Clinical Importance and Pathophysiological Role in Cancer

Document Type : Review Article

Authors

1 Department of Biology, School of Science, University of Isfahan, Isfahan, Iran

2 Assistant Professor, Department of Biology, School of Science, University of Isfahan, Isfahan, Iran

Abstract

Background: P-glycoprotein 170 is encoded by MDR1 gene and belongs to the ATP-binding cassette transporters (ABC) superfamily. This protein has important roles in cell physiology and its function in cancerous cells may contribute to failure treatment. The molecular structure of P-glycoprotein and its corresponding gene is introduced in this research. Moreover, the pathophysiological role of this protein and its effects on pharmacokinetics are discussed.Methods: EBSCO, Elsevier, PubMed and OVID databases were reviewed to introduce the most recent studies regarding p-glycoprotein, MDR1 and their clinical importance in health and disease. Authors’ novel findings regarding MDR1 and leukemia were also discussed.Findings: P-glycoprotein is naturally expressed in many tissues such as liver, intestine and brain. This protein is involved in many cellular processes such as inflammation, immune cell differentiation, detoxification and hormone secretion. Reduction of the treatment efficiency and the consecutive relapse due to drug resistance are the most important consequences of this protein function, and addressed as the most challenging obstacles in cancer treatment.Conclusion: P-glycoprotein is an important transporter with a protecting function in normal cell life. On the other hand, it may provide drug resistance in some cancerous cells. Comprehensive studies about MDR1 and P-glycoprotein 170 may provide novel approaches to new diagnostics and therapeutics.

Keywords

References

  1. Huls M, Russel FG, Masereeuw R. The role of ATP binding cassette transporters in tissue defense and organ regeneration. J Pharmacol Exp Ther 2009; 328(1): 3-9.
  2. Sauna ZE, Kim IW, Ambudkar SV. Genomics and the mechanism of P-glycoprotein (ABCB1). J Bioenerg Biomembr 2007; 39(5-6): 481-7.
  3. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. Oncogene 2003; 22(47): 7468-85.
  4. Jones PM, George AM. The ABC transporter structure and mechanism: perspectives on recent research. Cell Mol Life Sci 2004; 61(6): 682-99.
  5. Rosenberg MF, Callaghan R, Ford RC, Higgins CF. Structure of the multidrug resistance P-glycoprotein to 2.5 nm resolution determined by electron microscopy and image analysis. J Biol Chem 1997; 272(16): 10685-94.
  6. Cordon-Cardo C, O'Brien JP, Boccia J, Casals D, Bertino JR, Melamed MR. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 1990; 38(9): 1277-87.
  7. Mruk DD, Su L, Cheng CY. Emerging role for drug transporters at the blood-testis barrier. Trends Pharmacol Sci 2011; 32(2): 99-106.
  8. Al-Shawi MK, Omote H. The remarkable transport mechanism of P-glycoprotein: a multidrug transporter. J Bioenerg Biomembr 2005; 37(6): 489-96.
  9. Brinkmann U, Roots I, Eichelbaum M. Pharmacogenetics of the human drug-transporter gene MDR1: impact of polymorphisms on pharmacotherapy. Drug Discov Today 2001; 6(16): 835-9.
  10. Entezar-e-Ghaem M, Rahgozar S, Moafi AR. The methods to overcome ATP-binding cassette transporters-mediated multidrug resistance. J Isfahan Med Sch 2013; 30(213): 1919-34. [In Persian].
  11. Lage H. Reversal of MDR1/P-glycoprotein-mediated multidrug resistance by RNA interference. International Congress Series 2005; 1277: 144-53.
  12. Loo TW, Bartlett MC, Clarke DM. Suppressor mutations in the transmembrane segments of P-glycoprotein promote maturation of processing mutants and disrupt a subset of drug-binding sites. J Biol Chem 2007; 282(44): 32043-52.
  13. Wu CP, Calcagno AM, Ambudkar SV. Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies. Curr Mol Pharmacol 2008; 1(2): 93-105.
  14. Su L, Mruk DD, Cheng CY. Drug transporters, the blood-testis barrier, and spermatogenesis. J Endocrinol 2011; 208(3): 207-23.
  15. Hu YF, Qiu W, Liu ZQ, Zhu LJ, Liu ZQ, Tu JH, et al. Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation. Clin Exp Pharmacol Physiol 2006; 33(11): 1093-8.
  16. Couture L, Nash JA, Turgeon J. The ATP-binding cassette transporters and their implication in drug disposition: a special look at the heart. Pharmacol Rev 2006; 58(2): 244-58.
  17. Calado RT, Falcao RP, Garcia AB, Gabellini SM, Zago MA, Franco RF. Influence of functional MDR1 gene polymorphisms on P-glycoprotein activity in CD34+ hematopoietic stem cells. Haematologica 2002; 87(6): 564-8.
  18. Barnard JB, Richardson S, Sheldon S, Fildes J, Pravica V, Hutchinson IV, et al. The MDR1/ABCB1 gene, a high-impact risk factor for cardiac transplant rejection. Transplantation 2006; 82(12): 1677-82.
  19. Mealey KL. Therapeutic implications of the MDR-1 gene. J Vet Pharmacol Ther 2004; 27(5): 257-64.
  20. O'Brien FE, Dinan TG, Griffin BT, Cryan JF. Interactions between antidepressants and P-glycoprotein at the blood-brain barrier: clinical significance of in vitro and in vivo findings. Br J Pharmacol 2012; 165(2): 289-312.
  21. Linardi RL, Natalini CC. Multi-drug resistance (MDR1) gene and P-glycoprotein influence on pharmacokinetic and pharmacodymanic of therapeutic drugs. Cienc Rural 2006; 36(1): 336-41.
  22. Wind NS, Holen I. Multidrug resistance in breast cancer: from in vitro models to clinical studies. Int J Breast Cancer 2011; 2011: 967419.
  23. Levin GM, Ellingrod VL. P-Glycoprotein: Why this drug transporter may be clinically important. Current Psychiatry 2012; 11(3): 38-40.
  24. Farnood A, Naderi N, Moghaddam SJ, Noorinayer B, Firouzi F, Aghazadeh R, et al. The frequency of C3435T MDR1 gene polymorphism in Iranian patients with ulcerative colitis. Int J Colorectal Dis 2007; 22(9): 999-1003.
  25. Fromm MF. The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans. Adv Drug Deliv Rev 2002; 54(10): 1295-310.
  26. Drach D, Zhao S, Drach J, Mahadevia R, Gattringer C, Huber H, et al. Subpopulations of normal peripheral blood and bone marrow cells express a functional multidrug resistant phenotype. Blood 1992; 80(11): 2729-34.
  27. Fenart L, Buee-Scherrer V, Descamps L, Duhem C, Poullain MG, Cecchelli R, et al. Inhibition of P-glycoprotein: rapid assessment of its implication in blood-brain barrier integrity and drug transport to the brain by an in vitro model of the blood-brain barrier. Pharm Res 1998; 15(7): 993-1000.
  28. Kolwankar D, Glover DD, Ware JA, Tracy TS. Expression and function of ABCB1 and ABCG2 in human placental tissue. Drug Metab Dispos 2005; 33(4): 524-9.
  29. Kyle-Cezar F, Echevarria-Lima J, Rumjanek VM. Independent regulation of ABCB1 and ABCC activities in thymocytes and bone marrow mononuclear cells during aging. Scand J Immunol 2007; 66(2-3): 238-48.
  30. Frank MH, Denton MD, Alexander SI, Khoury SJ, Sayegh MH, Briscoe DM. Specific MDR1 P-glycoprotein blockade inhibits human alloimmune T cell activation in vitro. J Immunol 2001; 166(4): 2451-9.
  31. Klimecki WT, Futscher BW, Grogan TM, Dalton WS. P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood 1994; 83(9): 2451-58.
  32. Izawa A, Schatton T, Frank NY, Ueno T, Yamaura K, Pendse SS, et al. A novel in vivo regulatory role of P-glycoprotein in alloimmunity. Biochem Biophys Res Commun 2010; 394(3): 646-52.
  33. Machado CG, Calado RT, Garcia AB, Falcao RP. Age-related changes of the multidrug resistance P-glycoprotein function in normal human peripheral blood T lymphocytes. Braz J Med Biol Res 2003; 36(12): 1653-7.
  34. Abedi M, Rahgozar S. Importance of P-glycoprotein in neuroinflammation. Proceedings of the 1st International and 5th Annual Congress of Neurogenetic Diseases from Bed to Bench; 2011 23-25 Nov; Tehran, Iran.
  35. Takahashi S, Aiba K, Ito Y, Hatake K, Nakane M, Kobayashi T, et al. Pilot study of MDR1 gene transfer into hematopoietic stem cells and chemoprotection in metastatic breast cancer patients. Cancer Sci 2007; 98(10): 1609-16.
  36. Ernest S, Bello-Reuss E. Secretion of platelet-activating factor is mediated by MDR1 P-glycoprotein in cultured human mesangial cells. J Am Soc Nephrol 1999; 10(11): 2306-13.
  37. Grude P, Conti F, Mennecier D, Louvel A, Houssin D, Weill B, et al. MDR1 gene expression in hepatocellular carcinoma and the peritumoral liver of patients with and without cirrhosis. Cancer Lett 2002; 186(1): 107-13.
  38. Annaert PP, Turncliff RZ, Booth CL, Thakker DR, Brouwer KL. P-glycoprotein-mediated in vitro biliary excretion in sandwich-cultured rat hepatocytes. Drug Metab Dispos 2001; 29(10): 1277-83.
  39. Melaine N, Lienard MO, Dorval I, Le GC, Lejeune H, Jegou B. Multidrug resistance genes and p-glycoprotein in the testis of the rat, mouse, Guinea pig, and human. Biol Reprod 2002; 67(6): 1699-707.
  40. Su L, Mruk DD, Lui WY, Lee WM, Cheng CY. P-glycoprotein regulates blood-testis barrier dynamics via its effects on the occludin/zonula occludens 1 (ZO-1) protein complex mediated by focal adhesion kinase (FAK). Proc Natl Acad Sci U S A 2011; 108(49): 19623-8.
  41. Marques DS, Sandrini JZ, Boyle RT, Marins LF, Trindade GS. Relationships between multidrug resistance (MDR) and stem cell markers in human chronic myeloid leukemia cell lines. Leuk Res 2010; 34(6): 757-62.
  42. Leonard GD, Fojo T, Bates SE. The role of ABC transporters in clinical practice. Oncologist 2003; 8(5): 411-24.
  43. Abedi M, Rahgozar S. Drug resistance mechanisms in acute lymphoblastic leukemia. Proceeding of the 6th National Congress of Iranian Pediatric Hematology & Oncology Society; 2012 Feb 8-10; Ahvaz, Iran.
  44. Takakuwa O, Oguri T, Ozasa H, Uemura T, Kasai D, Miyazaki M, et al. Over-expression of MDR1 in amrubicinol-resistant lung cancer cells. Cancer Chemother Pharmacol 2011; 68(3): 669-76.
  45. Schondorf T, Scharl A, Kurbacher CM, Bien O, Becker M, Neumann R, et al. Amplification of the mdr1-gene is uncommon in recurrent ovarian carcinomas. Cancer Lett 1999; 146(2): 195-9.
  46. Pakbaz S, Torabi-Nezhad S, Mojtahed Jaberi F, Saalabian MJ, Rezazadeh S. Clinical significance of P-Glycoprotein immunohistochemistry and histomorphologic factors in patients with osteosarcoma. IRCMJ 2009; 11(3): 277-85.
  47. Campos L, Guyotat D, Archimbaud E, Calmard-Oriol P, Tsuruo T, Troncy J, et al. Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood 1992; 79(2): 473-6.
  48. Balatzenko G, Vundinti BR, Margarita G. Correlation between the type of bcr-abl transcripts and blood cell counts in chronic myeloid leukemia - a possible influence of mdr1 gene expression. Hematol Rep 2011; 3(1): e3.
  49. Svirnovski AI, Shman TV, Serhiyenka TF, Savitski VP, Smolnikova VV, Fedasenka UU. ABCB1 and ABCG2 proteins, their functional activity and gene expression in concert with drug sensitivity of leukemia cells. Hematology 2009; 14(4): 204-12.
  50. Abedi M, Rahgozar S, Moshtaghian J, Ghaedi K, Moafi A, Entezare Ghaem M, et al. MDR1 gene expression in acute lymphoblastic leukemia; Implications in pharmacokinetics and relapse. Res Pharm Sci 2012; 7(5): S690.
  51. Sakata S, Fujiwara M, Ohtsuka K, Kamma H, Nagane M, Sakamoto A, et al. ATP-binding cassette transporters in primary central nervous system lymphoma: decreased expression of MDR1 P-glycoprotein and breast cancer resistance protein in tumor capillary endothelial cells. Oncol Rep 2011; 25(2): 333-9.
  52. Abedi M, Rahgozar S. Role of p-glycoprotein in epilepsy drug resistance and its regulatory mechanisms. Proceedings of the 1st International and 5th Annual Congress of Neurogenetic Diseases from Bed to Bench; 2011 23-25 Nov; Tehran, Iran.
  53. Sisodiya SM, Lin WR, Harding BN, Squier MV, Thom M. Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. Brain 2002; 125(Pt 1): 22-31.
  54. Marchi N, Hallene KL, Kight KM, Cucullo L, Moddel G, Bingaman W, et al. Significance of MDR1 and multiple drug resistance in refractory human epileptic brain. BMC Med 2004; 2: 37.
  55. Lazarowski A, Czornyj L, Lubienieki F, Girardi E, Vazquez S, D'Giano C. ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. Epilepsia 2007; 48(Suppl 5): 140-9.
  56. Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics 2005; 15(10): 693-704.
  57. Hemauer SJ, Nanovskaya TN, Abdel-Rahman SZ, Patrikeeva SL, Hankins GD, Ahmed MS. Modulation of human placental P-glycoprotein expression and activity by MDR1 gene polymorphisms. Biochem Pharmacol 2010; 79(6): 921-5.
  58. Crouthamel MH, Wu D, Yang Z, Ho RJ. A novel MDR1 GT1292-3TG (Cys431Leu) genetic variation and its effect on P-glycoprotein biologic functions. AAPS J 2010; 12(4): 548-55.
  59. Mendes J, Martinho A, Simoes O, Mota A, Breitenfeld L, Pais L. Genetic polymorphisms in CYP3A5 and MDR1 genes and their correlations with plasma levels of tacrolimus and cyclosporine in renal transplant recipients. Transplant Proc 2009; 41(3): 840-2.
  60. Yu X, Xie H, Wei B, Zhang M, Wang W, Wu J, et al. Association of MDR1 gene SNPs and haplotypes with the tacrolimus dose requirements in Han Chinese liver transplant recipients. PLoS One 2011; 6(11): e25933.
Journal of Isfahan Medical School
Volume 31, Issue 228 - Serial Number 228
January and February 2013
Pages 274-293

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History

  • Receive Date: 23 December 2012
  • Revise Date: 01 November 2024
  • Accept Date: 06 April 2022

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