Investigation of MRP1 and ABCG2 Gene Expression in Chronic Myeloid Leukemia (CML) Patients
Abstract
Background: This study evaluated and compared the quantitative expression of Multidrug Resistance-associated Protein 1 (MRP1) and ATP Binding Cassette subfamily G member 2 ( ABCG2), two Multidrug Resistance (MDR) related genes, in 30 CML patients and 27 normal subjects. Methods: Total RNA was extracted from peripheral blood Mononuclear cells (MNCs) using the Trizol method. Then cDNAs were synthesized. Gene expression was quantified with Real-Time PCR System. Relative expression of target genes was calculated using the 2-ΔΔCt method. Results: High expression of MRP1 and ABCG2 mRNAs were detected in the patient's group. Intra-group comparisons also revealed increased expression of ABCG2 in Accelerated Phase (AP)-Blastic Crisis (BC) patients compared to Chronic Phase (CP) patients. Whereas, increased expression of MRP1 in AP-BC patients was not statistically significant. Conclusion: Considering the wide spectrum of (ATP Binding Cassette) ABC transporter superfamily substrates, they can play an important role in cell fate determination. High expression of MRP1 and ABCG2 genes can result in the efflux of therapeutic agents, and subsequent reduction in their intracellular concentration. This mechanism finally protects the cells from the therapeutic effects of medications. On the other hand, these transporters are able to export growth factors out of the cell. Such exported molecules may have a growth-inducing effect on adjacent cells. These are the possible mechanisms for the participation of MRP1 and ABCG2 genes in conferring drug resistance to CML cells.
1. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring. Am J Hematol. 2016;91(2):252-65.
2. McCafferty EH, Dhillon S, Deeks ED. Dasatinib: A Review in Pediatric Chronic Myeloid Leukemia. Paediatr Drugs. 2018;20(6):593-600.
3. Huang Y, Sadee W. Membrane transporters and channels in chemoresistance and -sensitivity of tumor cells. Cancer Lett. 2006;239(2):168-82.
4. Klappe K, Hummel I, Hoekstra D, Kok JW. Lipid dependence of ABC transporter localization and function. Chem Phys Lipids. 2009;161(2):57-64.
5. Wilkens S. Structure and mechanism of ABC transporters. F1000Prime Rep. 2015;7:14.
6. Albermann N, Schmitz-Winnenthal FH, Z'Graggen K, Volk C, Hoffmann MM, Haefeli WE, et al. Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. Biochem Pharmacol. 2005;70(6):949-58.
7. Fletcher JI, Williams RT, Henderson MJ, Norris MD, Haber M. ABC transporters as mediators of drug resistance and contributors to cancer cell biology. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2016;26:1-9.
8. Szakacs G, Annereau JP, Lababidi S, Shankavaram U, Arciello A, Bussey KJ, et al. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell. 2004;6(2):129-37.
9. Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol. 2005;204(3):216-37.
10. Solali S, Kaviani S, Movassaghpour AA, Aliparasti MR. Real-time polymerase chain reaction testing for quantitative evaluation of hOCT1 and MDR1 expression in patients with chronic myeloid leukemia resistant to imatinib. Laboratory Medicine. 2013 Feb 1;44(1):13-9.
11. Mercier C, Masseguin C, Roux F, Gabrion J, Scherrmann JM. Expression of P-glycoprotein (ABCB1) and Mrp1 (ABCC1) in adult rat brain: focus on astrocytes. Brain Res. 2004;1021(1):32-40.
12. Meenakshi Sundaram DN, Jiang X, Brandwein JM, Valencia-Serna J, Remant KC, Uludag H. Current outlook on drug resistance in chronic myeloid leukemia (CML) and potential therapeutic options. Drug Discov Today. 2019;24(7):1355-69.
13. Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. The lancet oncology. 2007 Nov 1;8(11):1018-29.
14. Melo JV, Chuah C. Resistance to imatinib mesylate in chronic myeloid leukaemia. Cancer Lett. 2007;249(2):121-32.
15. Linev AJ, Ivanov HJ, Zhelyazkov IG, Ivanova H, Goranova-Marinova VS, Stoyanova VK. Mutations Associated with Imatinib Mesylate Resistance - Review. Folia Med (Plovdiv). 2018;60(4):617-23.
16. Keramatinia A, Ahadi A, Akbari ME, Mohseny M, Mosavi Jarahi A, Bahadori-Monfared A, et al. The roles of DNA epigenetics and clinical significance in Chronic Myeloid Leukemia: a review. Cell Mol Biol (Noisy-le-grand). 2018;64(9):58-63.
17. Chang G. Multidrug resistance ABC transporters. FEBS Lett. 2003;555(1):102-5.
18. Maia RC, Vasconcelos FC, Souza PS, Rumjanek VM. Towards Comprehension of the ABCB1/P-Glycoprotein Role in Chronic Myeloid Leukemia. Molecules. 2018;23(1).
19. Chapuy B, Panse M, Radunski U, Koch R, Wenzel D, Inagaki N, et al. ABC transporter A3 facilitates lysosomal sequestration of imatinib and modulates susceptibility of chronic myeloid leukemia cell lines to this drug. Haematologica. 2009;94(11):1528-36.
20. Chen JR, Jia XH, Wang H, Yi YJ, Wang JY, Li YJ. Timosaponin A-III reverses multi-drug resistance in human chronic myelogenous leukemia K562/ADM cells via downregulation of MDR1 and MRP1 expression by inhibiting PI3K/Akt signaling pathway. International journal of oncology. 2016 May 1;48(5):2063-70.
21. Park SH, Park CJ, Kim DY, Lee BR, Kim YJ, Cho YU, Jang S. MRP1 and P-glycoprotein expression assays would be useful in the additional detection of treatment non-responders in CML patients without ABL1 mutation. Leukemia research. 2015 Oct 1;39(10):1109-16.
22. de Lima LT, Vivona D, Bueno CT, Hirata RD, Hirata MH, Luchessi AD, et al. Reduced ABCG2 and increased SLC22A1 mRNA expression are associated with imatinib response in chronic myeloid leukemia. Med Oncol. 2014;31(3):851.
23. Cole SP. Multidrug resistance protein 1 (MRP1, ABCC1), a "multitasking" ATP-binding cassette (ABC) transporter. J Biol Chem. 2014;289(45):30880-8.
24. Haber M, Smith J, Bordow SB, Flemming C, Cohn SL, London WB, et al. Association of high-level MRP1 expression with poor clinical outcome in a large prospective study of primary neuroblastoma. J Clin Oncol. 2006;24(10):1546-53.
25. Fletcher JI, Haber M, Henderson MJ, Norris MD. ABC transporters in cancer: more than just drug efflux pumps. Nature Reviews Cancer. 2010 Feb;10(2):147-56.
26. Xie J, Jin B, Li DW, Shen B, Cong N, Zhang TZ, Dong P. ABCG2 regulated by MAPK pathways is associated with cancer progression in laryngeal squamous cell carcinoma. American journal of cancer research. 2014;4(6):698-709.
27. Chen Z, Liu F, Ren Q, Zhao Q, Ren H, Lu S, Zhang L, Han Z. Suppression of ABCG2 inhibits cancer cell proliferation. International journal of cancer. 2010 Feb 15;126(4):841-51.
28. Nagahashi M, Takabe K, Terracina KP, Soma D, Hirose Y, Kobayashi T, Matsuda Y, Wakai T. Sphingosine-1-phosphate transporters as targets for cancer therapy. BioMed research international. 2014 Jan 1;2014.
29. Takahashi K, Kimura Y, Nagata K, Yamamoto A, Matsuo M, Ueda K. ABC proteins: key molecules for lipid homeostasis. Med Mol Morphol. 2005;38(1):2-12.
30. De Waart DR, Paulusma CC, Kunne C, Oude Elferink RP. Multidrug resistance associated protein 2 mediates transport of prostaglandin E2. Liver International. 2006 Apr;26(3):362-8.
31. Vander Borght S, Komuta M, Libbrecht L, Katoonizadeh A, Aerts R, Dymarkowski S, Verslype C, Nevens F, Roskams T. Expression of multidrug resistance‐associated protein 1 in hepatocellular carcinoma is associated with a more aggressive tumour phenotype and may reflect a progenitor cell origin. Liver International. 2008 Nov;28(10):1370-80.
32. Filipits M, Suchomel RW, Dekan G, Haider K, Valdimarsson G, Depisch D, Pirker R. MRP and MDR1 gene expression in primary breast carcinomas. Clinical Cancer Research. 1996 Jul 1;2(7):1231-7.
33. Greenberg PL, Lee SJ, Advani R, Tallman MS, Sikic BI, Letendre L, Dugan K, Lum B, Chin DL, Dewald G, Paietta E. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2004 Mar 15;22(6):1078.
34. Scharenberg CW, Harkey MA, Torok-Storb B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood, The Journal of the American Society of Hematology. 2002 Jan 15;99(2):507-12.
35. Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ, et al. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci U S A. 2002;99(24):15649-54.
36. Zhou S, Morris JJ, Barnes Y, Lan L, Schuetz JD, Sorrentino BP. Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo. Proceedings of the National Academy of Sciences. 2002 Sep 17;99(19):12339-44.
37. Robey RW, To KK, Polgar O, Dohse M, Fetsch P, Dean M, Bates SE. ABCG2: a perspective. Advanced drug delivery reviews. 2009 Jan 31;61(1):3-13.
38. Oostendorp RL, Buckle T, Beijnen JH, van Tellingen O, Schellens JH. The effect of P-gp (Mdr1a/1b), BCRP (Bcrp1) and P-gp/BCRP inhibitors on the in vivo absorption, distribution, metabolism and excretion of imatinib. Investigational new drugs. 2009 Feb 1;27(1):31-40.
39. Bihorel S, Camenisch G, Lemaire M, Scherrmann JM. Influence of breast cancer resistance protein (Abcg2) and p-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec) across the mouse blood-brain barrier. J Neurochem. 2007;102(6):1749-57.
40. Kuss BJ, Corbo M, Lau WM, Fennell DA, Dean NM, Cotter FE. In vitro and in vivo downregulation of MRP1 by antisense oligonucleotides: a potential role in neuroblastoma therapy. Int J Cancer. 2002;98(1):128-33.
41. Steinbach D, Sell W, Voigt A, Hermann J, Zintl F, Sauerbrey A. BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia. Leukemia. 2002 Aug;16(8):1443-7.
42. Benderra Z, Faussat AM, Sayada L, Perrot JY, Chaoui D, Marie JP, et al. Breast cancer resistance protein and P-glycoprotein in 149 adult acute myeloid leukemias. Clin Cancer Res. 2004;10(23):7896-902.
43. Balabanov S, Gontarewicz A, Keller G, Raddrizzani L, Braig M, Bosotti R, et al. Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro. PLoS One. 2011;6(4):e19164.
2. McCafferty EH, Dhillon S, Deeks ED. Dasatinib: A Review in Pediatric Chronic Myeloid Leukemia. Paediatr Drugs. 2018;20(6):593-600.
3. Huang Y, Sadee W. Membrane transporters and channels in chemoresistance and -sensitivity of tumor cells. Cancer Lett. 2006;239(2):168-82.
4. Klappe K, Hummel I, Hoekstra D, Kok JW. Lipid dependence of ABC transporter localization and function. Chem Phys Lipids. 2009;161(2):57-64.
5. Wilkens S. Structure and mechanism of ABC transporters. F1000Prime Rep. 2015;7:14.
6. Albermann N, Schmitz-Winnenthal FH, Z'Graggen K, Volk C, Hoffmann MM, Haefeli WE, et al. Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. Biochem Pharmacol. 2005;70(6):949-58.
7. Fletcher JI, Williams RT, Henderson MJ, Norris MD, Haber M. ABC transporters as mediators of drug resistance and contributors to cancer cell biology. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2016;26:1-9.
8. Szakacs G, Annereau JP, Lababidi S, Shankavaram U, Arciello A, Bussey KJ, et al. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell. 2004;6(2):129-37.
9. Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol. 2005;204(3):216-37.
10. Solali S, Kaviani S, Movassaghpour AA, Aliparasti MR. Real-time polymerase chain reaction testing for quantitative evaluation of hOCT1 and MDR1 expression in patients with chronic myeloid leukemia resistant to imatinib. Laboratory Medicine. 2013 Feb 1;44(1):13-9.
11. Mercier C, Masseguin C, Roux F, Gabrion J, Scherrmann JM. Expression of P-glycoprotein (ABCB1) and Mrp1 (ABCC1) in adult rat brain: focus on astrocytes. Brain Res. 2004;1021(1):32-40.
12. Meenakshi Sundaram DN, Jiang X, Brandwein JM, Valencia-Serna J, Remant KC, Uludag H. Current outlook on drug resistance in chronic myeloid leukemia (CML) and potential therapeutic options. Drug Discov Today. 2019;24(7):1355-69.
13. Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. The lancet oncology. 2007 Nov 1;8(11):1018-29.
14. Melo JV, Chuah C. Resistance to imatinib mesylate in chronic myeloid leukaemia. Cancer Lett. 2007;249(2):121-32.
15. Linev AJ, Ivanov HJ, Zhelyazkov IG, Ivanova H, Goranova-Marinova VS, Stoyanova VK. Mutations Associated with Imatinib Mesylate Resistance - Review. Folia Med (Plovdiv). 2018;60(4):617-23.
16. Keramatinia A, Ahadi A, Akbari ME, Mohseny M, Mosavi Jarahi A, Bahadori-Monfared A, et al. The roles of DNA epigenetics and clinical significance in Chronic Myeloid Leukemia: a review. Cell Mol Biol (Noisy-le-grand). 2018;64(9):58-63.
17. Chang G. Multidrug resistance ABC transporters. FEBS Lett. 2003;555(1):102-5.
18. Maia RC, Vasconcelos FC, Souza PS, Rumjanek VM. Towards Comprehension of the ABCB1/P-Glycoprotein Role in Chronic Myeloid Leukemia. Molecules. 2018;23(1).
19. Chapuy B, Panse M, Radunski U, Koch R, Wenzel D, Inagaki N, et al. ABC transporter A3 facilitates lysosomal sequestration of imatinib and modulates susceptibility of chronic myeloid leukemia cell lines to this drug. Haematologica. 2009;94(11):1528-36.
20. Chen JR, Jia XH, Wang H, Yi YJ, Wang JY, Li YJ. Timosaponin A-III reverses multi-drug resistance in human chronic myelogenous leukemia K562/ADM cells via downregulation of MDR1 and MRP1 expression by inhibiting PI3K/Akt signaling pathway. International journal of oncology. 2016 May 1;48(5):2063-70.
21. Park SH, Park CJ, Kim DY, Lee BR, Kim YJ, Cho YU, Jang S. MRP1 and P-glycoprotein expression assays would be useful in the additional detection of treatment non-responders in CML patients without ABL1 mutation. Leukemia research. 2015 Oct 1;39(10):1109-16.
22. de Lima LT, Vivona D, Bueno CT, Hirata RD, Hirata MH, Luchessi AD, et al. Reduced ABCG2 and increased SLC22A1 mRNA expression are associated with imatinib response in chronic myeloid leukemia. Med Oncol. 2014;31(3):851.
23. Cole SP. Multidrug resistance protein 1 (MRP1, ABCC1), a "multitasking" ATP-binding cassette (ABC) transporter. J Biol Chem. 2014;289(45):30880-8.
24. Haber M, Smith J, Bordow SB, Flemming C, Cohn SL, London WB, et al. Association of high-level MRP1 expression with poor clinical outcome in a large prospective study of primary neuroblastoma. J Clin Oncol. 2006;24(10):1546-53.
25. Fletcher JI, Haber M, Henderson MJ, Norris MD. ABC transporters in cancer: more than just drug efflux pumps. Nature Reviews Cancer. 2010 Feb;10(2):147-56.
26. Xie J, Jin B, Li DW, Shen B, Cong N, Zhang TZ, Dong P. ABCG2 regulated by MAPK pathways is associated with cancer progression in laryngeal squamous cell carcinoma. American journal of cancer research. 2014;4(6):698-709.
27. Chen Z, Liu F, Ren Q, Zhao Q, Ren H, Lu S, Zhang L, Han Z. Suppression of ABCG2 inhibits cancer cell proliferation. International journal of cancer. 2010 Feb 15;126(4):841-51.
28. Nagahashi M, Takabe K, Terracina KP, Soma D, Hirose Y, Kobayashi T, Matsuda Y, Wakai T. Sphingosine-1-phosphate transporters as targets for cancer therapy. BioMed research international. 2014 Jan 1;2014.
29. Takahashi K, Kimura Y, Nagata K, Yamamoto A, Matsuo M, Ueda K. ABC proteins: key molecules for lipid homeostasis. Med Mol Morphol. 2005;38(1):2-12.
30. De Waart DR, Paulusma CC, Kunne C, Oude Elferink RP. Multidrug resistance associated protein 2 mediates transport of prostaglandin E2. Liver International. 2006 Apr;26(3):362-8.
31. Vander Borght S, Komuta M, Libbrecht L, Katoonizadeh A, Aerts R, Dymarkowski S, Verslype C, Nevens F, Roskams T. Expression of multidrug resistance‐associated protein 1 in hepatocellular carcinoma is associated with a more aggressive tumour phenotype and may reflect a progenitor cell origin. Liver International. 2008 Nov;28(10):1370-80.
32. Filipits M, Suchomel RW, Dekan G, Haider K, Valdimarsson G, Depisch D, Pirker R. MRP and MDR1 gene expression in primary breast carcinomas. Clinical Cancer Research. 1996 Jul 1;2(7):1231-7.
33. Greenberg PL, Lee SJ, Advani R, Tallman MS, Sikic BI, Letendre L, Dugan K, Lum B, Chin DL, Dewald G, Paietta E. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2004 Mar 15;22(6):1078.
34. Scharenberg CW, Harkey MA, Torok-Storb B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood, The Journal of the American Society of Hematology. 2002 Jan 15;99(2):507-12.
35. Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ, et al. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci U S A. 2002;99(24):15649-54.
36. Zhou S, Morris JJ, Barnes Y, Lan L, Schuetz JD, Sorrentino BP. Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo. Proceedings of the National Academy of Sciences. 2002 Sep 17;99(19):12339-44.
37. Robey RW, To KK, Polgar O, Dohse M, Fetsch P, Dean M, Bates SE. ABCG2: a perspective. Advanced drug delivery reviews. 2009 Jan 31;61(1):3-13.
38. Oostendorp RL, Buckle T, Beijnen JH, van Tellingen O, Schellens JH. The effect of P-gp (Mdr1a/1b), BCRP (Bcrp1) and P-gp/BCRP inhibitors on the in vivo absorption, distribution, metabolism and excretion of imatinib. Investigational new drugs. 2009 Feb 1;27(1):31-40.
39. Bihorel S, Camenisch G, Lemaire M, Scherrmann JM. Influence of breast cancer resistance protein (Abcg2) and p-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec) across the mouse blood-brain barrier. J Neurochem. 2007;102(6):1749-57.
40. Kuss BJ, Corbo M, Lau WM, Fennell DA, Dean NM, Cotter FE. In vitro and in vivo downregulation of MRP1 by antisense oligonucleotides: a potential role in neuroblastoma therapy. Int J Cancer. 2002;98(1):128-33.
41. Steinbach D, Sell W, Voigt A, Hermann J, Zintl F, Sauerbrey A. BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia. Leukemia. 2002 Aug;16(8):1443-7.
42. Benderra Z, Faussat AM, Sayada L, Perrot JY, Chaoui D, Marie JP, et al. Breast cancer resistance protein and P-glycoprotein in 149 adult acute myeloid leukemias. Clin Cancer Res. 2004;10(23):7896-902.
43. Balabanov S, Gontarewicz A, Keller G, Raddrizzani L, Braig M, Bosotti R, et al. Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro. PLoS One. 2011;6(4):e19164.
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Issue | Vol 12 No 2 (2020) | |
Section | Original Articles | |
DOI | https://doi.org/10.18502/bccr.v12i2.5755 | |
Keywords | ||
ABCG2 MRP1 CML Imatinib Gene expression |
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How to Cite
1.
Solali S, Fardi M, Almasi S, Aliparasti MR. Investigation of MRP1 and ABCG2 Gene Expression in Chronic Myeloid Leukemia (CML) Patients. Basic Clin Cancer Res. 2020;12(2):56-69.