The Role of Membrane Transporters in Cellular Resistance of Pancreatic Carcinoma to Gemcitabine
Authors:
B. Mohelníková‑ duchoňová 1,2; P. Souček 1
Authors‘ workplace:
Laboratoře toxikogenomiky, Státní zdravotní ústav, Praha
1; I. lékařská fakulta Univerzity Karlovy, Praha
2
Published in:
Klin Onkol 2010; 23(5): 306-310
Category:
Reviews
Overview
Backgrounds:
Pancreatic carcinoma is one of the most serious forms of cancer, with a very high mortality rate, and is the fourth leading cause of cancer‑related death in the Czech Republic. The etiology and molecular pathogenesis of the disease is still poorly understood. Gemcitabine is a cytotoxic nucleoside analog, which is widely used in the treatment of malignancies, and in particular in pancreatic carcinoma. Interindividual differences in gemcitabine pharmacokinetics and pharmacodynamics have been demonstrated, which can significantly influence the outcome of the therapy in thus treated patients. Resistance developed to nucleoside analogs limits their clinical use, just like in the case of any other cytostatics.
Aim:
This review summarizes available data concerning the membrane proteins involved in the transport mechanism of gemcitabine through cellular membrane, and their role in the cellular resistance of pancreatic carcinoma to gemcitabine.
Key words:
pancreatic cancer – membrane transport proteins – ATP‑binding cassette transporters – nucleoside transport proteins – gemcitabine
Sources
1. Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta‑analysis. JAMA 1995; 273(20): 1605– 1609.
2. Mukesh V. Pancreatic cancer epidemiology. Technol Cancer Res Treat 2005; 4: 295– 301.
3. Klener P et al. Klinická onkologie. Praha: Galén 2002: 429– 433.
4. Almoguera C, Shibata D, Forrester K et al. Most human carcinomas of the exocrine pancreas contain mutant c‑ K‑ ras genes. Cell 1988; 53(4): 49– 54.
5. Li D, Xie K, Wolff R et al. Pancreatic cancer. Lancet 2004; 363(9414): 1049– 1057.
6. Porta M, Malats N, Jariod M et al. Serum concentrations of organochlorine compounds and K‑ ras mutations in exocrine pancreatic cancer. PANKRAS II Study Group. Lancet 1999; 354(9196): 2125– 2129.
7. Terhune PG, Phifer DM, Tosteson TDet al. K‑ ras mutation in focal proliferative lesions of human pancreas. Cancer Epidemiol Biomarkers Prev 1998; 7(6): 515– 521.
8. Serrano M, Lin AW, McCurrach ME et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88(5): 593– 602.
9. Hirano T, Shino Y, Saito T et al. Dominant negative MEKK1 inhibits survival of pancreatic cancer cells.Oncogene 2002; 21(38): 5923– 5928.
10. Brummelkamp TR, Bernards R, Agami R. A system for stable expression of short interfering RNAs in mammalian cells. Science 2002; 296(5567): 550– 553.
11. Kawesha A, Ghaneh P, Skar R et al. K‑ ras oncogene subtype mutations are associated with survival but not expression of p53, p16(INK4A), p21(WAF‑ 1), cyclin D1, erbB‑ 2 and erbB‑ 3 in resected pancreatic ductal adenocarcinoma. Int J Cancer 2000; 89(6): 469– 474.
12. Finkelstein SD, Przygodzki R, Pricolo VE et al. Genotypic classification of colorectal adenocarcinoma. Biologic behavior correlates with K‑ ras‑ 2 mutation type. Cancer 1993; 71(12): 3827– 3388.
13. Pannala R, Basu A, Petersen GM et. al. New‑ onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol 2009; 10(1): 88– 95.
14. Matsubara J, Ono M, Honda K et al. Survival prediction for pancreatic cancer patients receiving gemcitabine treatment. Mol Cell Proteomics 2010; 9(4): 695– 704.
15. Heinemann V, Hertel LW, Grindey GB et al. Comparison of the cellular pharmacokinetics and toxicity of 2’,2’‑ difluorodeoxycytidine and 1‑beta‑D‑ arabinofuranosylcytosine. Cancer Res 1988; 48(14): 4024– 4031.
16. Plunkett W, Huang P, Xu YZ et al. Gemcitabine: metabolism, mechanisms of action, and self‑ potentiation. Semin Oncol 1995; 22: 3– 10.
17. Erkan M, Kleeff J, Esposito I et al. Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis. Oncogene 2005; 24(27): 4421– 4432.
18. Baldwin SA, Beal PR, Yao SY et al. The equilibrative nucleoside transporter family, SLC29. Pflugers Arch 2004;447: 735– 743.
19. Gray JH, Owen RP, Giacomini KM. The concentrative nucleoside transporter family, SLC28. Pflugers Arch 2004; 447(5): 728– 734
20. Mackey JR, Mani RS, Selner M et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 1998; 58(19): 4349– 4357.
21. García‑ Manteiga J, Molina‑ Arcas M, Casado FJ et al. Nucleoside transporter profiles in human pancreatic cancer cells: role of hCNT1 in 2’,2’‑ difluorodeoxycytidine‑ induced cytotoxicity. Clin Can Res 2003; 9(13): 5000– 5008.
22. Bergman AM, Pinedo HM, Talianidis I et al. Increased sensitivity to gemcitabine of P‑ glycoprotein and multidrug resistance‑associated protein‑overexpressing human cancer cell lines. Br J Cancer 2003; 88(12): 1963– 1970.
23. Spratlin J, Sangha R, Glubrecht D et al. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine‑treated pancreas adenocarcinoma. Clin Cancer Res 2004; 10(20): 6956– 6961.
24. Giovannetti E, Del Tacca M, Mey V et al. Transcription analysis of human equilibrative nucleoside transporter‑ 1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res 2006; 66(7): 3928– 3935.
25. Chen CJ, Chin JE, Ueda K et al. Internal duplication and homology with bacterial transport proteins in the mdr1 (P‑ glycoprotein) gene from multidrug‑resistant human cells. Cell 1986; 47(3): 381– 389.
26. Cole SP, Bhardwaj G, Gerlach JH et al. Overexpression of a transporter gene in a multidrug‑resistant human lung cancer cell line. Science 1992; 258(5088): 1650– 1654.
27. Ambudkar SV, Kimchi‑ Sarfaty CH, Sauna ZE et al. P‑ glycoprotein: from genomics to mechanism. Oncogene 2003; 22(47): 7468– 7485.
28. Borst P, Evers R, Kool M et al. A family of drug transporters: the multidrug resistance‑associated proteins. J Natl Cancer Inst 2000; 92(16):1295– 1302.
29. Olempska M, Eisenach PA, Ammerpohl O et. al. Detection of tumor stem cell markers in pancreatic carcinoma cell lines. Hepatobiliary Pancreat Dis Int 2007; 6(1): 92– 97.
30. Rabow AA, Shoemaker RH, Sausville EA et al. Mining the National Cancer Institute’s tumor‑ screening database: identification of compounds with similar cellular activities. J Med Chem 2002; 45(4): 818– 840.
31. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP‑ dependent transporters. Nat Rev Cancer 2002; 2(1): 48– 58.
32. Marzolini C, Paus E, Buclin T et al. Polymorphisms in human MDR1 (P‑ glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 2004; 75(1): 13– 33.
33. Takane H, Kobayashi D, Hirota T et al. Haplotype‑ oriented genetic analysis and functional assessment of promoter variants in the MDR1 (ABCB1) gene. J Pharmacol Exp Ther 2004; 311(3): 1179– 1187.
34. Taniguchi S, Mochida Y, Uchiumi T et al. Genetic polymorphism at the 5’ regulatory region of multidrug resistance 1 (MDR1) and its association with interindividual variation of expression level in the colon. Mol Cancer Ther 2003; 2(12): 1351– 1359.
35. Suwa H, Ohshio G, Shinji A et al. Immunohistochemical localization of P‑ glycoprotein and expression of the multidrug resistance‑ 1 gene in human pancreatic cancer: relevance to indicator of better prognosis. Jpn J Cancer Res 1996; 87(6): 641– 649.
36. Lu Z, Kleeff J, Shrikhande S et al. Expression of the multidrug‑resistance 1 (MDR1) gene and prognosis in human pancreatic cancer. Pancreas 2000; 21(3): 240– 247.
37. Václavíková R, Nordgard SH, Alnaes GI et al. Single nucleotide polymorphisms in the multidrug resistance gene 1 (ABCB1): effects on its expression and clinicopathological characteristics in breast cancer patients. Pharmacogenet Genomics 2008; 18(3): 263– 273.
38. Reid G, Wielinga P, Zelcer N et al. The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Mol Pharmacol 2003; 63: 1094– 1103.
39. Chen ZS, Guo Y, Belinsky MG et al. Transport of bile acids, sulfated steroids, estradiol 17‑beta‑D‑ glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11). Mol Pharmacol 2005; 67(2): 545– 557.
40. Wijnholds J, Mol CA, van Deemter L et al. Multidrug‑resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci USA 2000; 97(13): 7476– 7481.
41. Konig J, Hartel M, Nies AT et al. Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. Int J Cancer 2005; 115(3): 359– 367.
42. Oguri T, Achiwa H, Sato S et al. 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 2006; 5(7): 1800– 1806.
43. Kage K, Fujita T, Sugimoto Y. Role of Cys‑ 603 in dimer/ oligodimer formation of the breast cancer resistance protein BCRP/ ACG2. Cancer Sci 2005; 96(12): 866– 872.
44. de Wolf C, Jansen R, Yamaguchi H et al. Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides. Mol Cancer Ther 2008; 7(9): 3092– 3102.
45. Doyle LA, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 2003; 22(47): 7340– 7358.
46. Zhou J, Wang CY, Liu T et al. Persistence of side population cells with high drug efflux capacity in pancreatic cancer. World J Gastroenterol 2008, 14(6): 925– 930.
47. Shi Z, Peng XX, Kim IW et al. Erlotinib (Tarceva, OSI‑ 774) antagonizes ATP‑binding cassette subfamily B member 1 and ATP‑binding cassette subfamily G member 2– mediated drug resistance. Cancer Res 2007; 67(22): 11012– 11020.
48. Marchetti S, de Vries NA, Buckle T et al. Effect of the ATP‑binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1- / ‑ / Mdr1a/ 1b‑ / ‑ (triple- knockout) and wild‑type mice. Mol Cancer Ther 2008; 7(8): 2280– 2287.
49. Ardavanis A, Kountourakis P, Karagiannis A et al. Biweekly gemcitabine (GEM) in combination with erlotinib (ERL): an active and convenient regimen for advanced pancreatic cancer. Anticancer Res 2009; 29(12): 5211– 5217.
50. Guo Y, Kotova E, Chen Z et al. 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 Biol Chem 2003; 278(32): 29509– 29514.
51. Takenaka K, Morgan JA, Scheffer GL et al. Substrate overlap between Mrp4 and Abcg2/ Bcrp affects purine analogue drug cytotoxicity and tissue distribution. Cancer Res 2007; 67(14): 6965– 6972.
52. Okazaki T, Javle M, Tanaka M et al. Single nucleotide polymorphisms of gemcitabine metabolic genes and pancreatic cancer survival and drug toxicity. Clin Cancer Res 2010; 16(1): 320– 329.
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