Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor

International Journal of Molecular Medicine

Volumn 30, Issue 6, 2012, Pages 1505-1511

  Gray, Steven G ^a   Baird, Anne Marie ^a   O'Kelly, Fardod ^b   Nikolaidis, Georgios ^c   Almgren, Malin ^d   Meunier, Armelle ^b   Dockry, Eilis ^a   Hollywood, Donal ^b   Ekström, Tomas J ^d   Perry, Antoinette S ^b   O'Byrne, Kenneth J ^a,b  

^a TRINITY COLLEGE DUBLIN   (Ireland)

^b ST JAMES S HOSPITAL   (Ireland)

^c UNIVERSITY OF LIVERPOOL   (United Kingdom)

^d KAROLINSKA INSTITUTE   (Sweden)

Author keywords

Cancer; DNA methyltransferase; DNMT inhibitor; Epigenetics; Gemcitabine

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; DNA METHYLTRANSFERASE; DNA METHYLTRANSFERASE 1; GEMCITABINE; GLUTATHIONE TRANSFERASE P1;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL STRAIN; CONTROLLED STUDY; CPG ISLAND; DNA METHYLATION; DRUG STRUCTURE; ENZYME ACTIVITY; GENE SILENCING; PRIORITY JOURNAL; PYROSEQUENCING; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION;

ANTIMETABOLITES, ANTINEOPLASTIC; AZACITIDINE; CELL LINE, TUMOR; CPG ISLANDS; DEOXYCYTIDINE; DNA (CYTOSINE-5-)-METHYLTRANSFERASE; DNA METHYLATION; ENZYME STABILITY; EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION, NEOPLASTIC; GENE SILENCING; HISTONE DEACETYLASE 1; HUMANS; PROMOTER REGIONS, GENETIC; TUMOR SUPPRESSOR PROTEINS; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-1;

EID: 84869418432     PISSN: 11073756     EISSN: 1791244X     Source Type: Journal    
DOI: 10.3892/ijmm.2012.1138     Document Type: Article

References (40)

1. Hidalgo M: Pancreatic cancer. N Engl J Med 362: 1605-1617, 2010.
2. DeVita VT Jr: A step in the right direction. Nat Clin Pract Oncol 3: 641, 2006.
3. Tkaczuk KH: Review of the contemporary cytotoxic and biologic combinations available for the treatment of metastatic breast cancer. Clin Ther 31: 2273-2289, 2009.
4. Goffin J, L acchetti C, E llis P M, U ng YC a nd E vans W K: First-line systemic chemotherapy in the treatment of advanced non-small cell lung cancer: a systematic review. J Thorac Oncol 5: 260-274, 2010.
5. Nagel S, Califano R, Thatcher N and Blackhall F: Gemcitabine and carboplatin in combination for the treatment of advanced, metastatic, non-small cell lung cancer. Expert Opin Pharmacother 8: 3265-3275, 2007.
6. Fennell DA, Gaudino G, O'Byrne KJ, Mutti L and van Meerbeeck J: Advances in the systemic therapy of malignant pleural mesothelioma. Nat Clin Pract Oncol 5: 136-147, 2008.
7. Ray M and Kindler HL: Malignant pleural mesothelioma: an update on biomarkers and treatment. Chest 136: 888-896, 2009.
8. Jantscheff P, Esser N, Graeser R, et al: Liposomal gemcitabine (GemLip)-efficient drug against hormone-refractory Du145 and PC-3 prostate cancer xenografts. Prostate 69: 1151-1163, 2009.
9. Jantscheff P, Ziroli V, Esser N, et al: Anti-metastatic effects of liposomal gemcitabine in a human orthotopic LNCaP prostate cancer xenograft model. Clin Exp Metastasis 26: 981-992, 2009.
10. Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R and Gandhi V: Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol 22 (Suppl 11): 3-10, 1995.
11. Lawless MW, Norris S, O'Byrne KJ and Gray SG: Targeting histone deacetylases for the treatment of disease. J Cell Mol Med 13: 826-852, 2009.
12. O'Byrne KJ, Barr MP and Gray SG: The role of epigenetics in resistance to cisplatin chemotherapy in lung cancer. Cancers 3: 1426-1453, 2011.
13. Cai D, Shames DS, Raso MG, et al: Steroid receptor coactivator-3 expression in lung cancer and its role in the regulation of cancer cell survival and proliferation. Cancer Res 70: 6477-6485, 2010.
14. Hajji N, Wallenborg K, Vlachos P, Fullgrabe J, Hermanson O and Joseph B: Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide. Oncogene 29: 2192-2204, 2010.
15. Zhao W, Zhang Q, Kang X, Jin S and Lou C: AIB1 is required for the acquisition of epithelial growth factor receptor-mediated tamoxifen resistance in breast cancer cells. Biochem Biophys Res Commun 380: 699-704, 2009.
16. Baylin SB and Jones PA: A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer 11: 726-734, 2011.
17. Gore SD, Jones C and Kirkpatrick P: Decitabine. Nat Rev Drug Discov 5: 891-892, 2006. (Pubitemid 44660602)
18. Kaminskas E, Farrell A, Abraham S, et al: Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 11: 3604-3608, 2005. (Pubitemid 40685574)
19. Yokochi T and Robertson KD: Doxorubicin inhibits DNMT1, resulting in conditional apoptosis. Mol Pharmacol 66: 1415-1420, 2004. (Pubitemid 39564768)
20. Gray SG, Al-Sarraf N, Baird AM, Cathcart MC, McGovern E and O'Byrne KJ: Regulation of EP receptors in non-small cell lung cancer by epigenetic modifications. Eur J Cancer 45: 3087-3097, 2009.
21. Laird PW, Zijderveld A, Linders K, Rudnicki MA, Jaenisch R and Berns A: Simplified mammalian DNA isolation procedure. Nucleic Acids Res 19: 4293, 1991.
22. Daskalos A, Logotheti S, Markopoulou S, et al: Global DNA hypomethylation-induced DeltaNp73 transcriptional activation in non-small cell lung cancer. Cancer Lett 300: 79-86, 2011.
23. Daskalos A, Nikolaidis G, Xinarianos G, et al: Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer. Int J Cancer 124: 81-87, 2009.
24. Daskalos A, Oleksiewicz U, Filia A, et al: UHRF1-mediated tumor suppressor gene inactivation in nonsmall cell lung cancer. Cancer 117: 1027-1037, 2011.
25. He B, Lee AY, Dadfarmay S, et al: Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in beta-catenin-deficient human mesothelioma cells. Cancer Res 65: 743-748, 2005. (Pubitemid 40216431)
26. Lee AY, He B, You L, et al: Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma. Oncogene 23: 6672-6676, 2004. (Pubitemid 39265531)
27. Nelson WG, De Marzo AM and Yegnasubramanian S: Epigenetic alterations in human prostate cancers. Endocrinology 150: 3991-4002, 2009.
28. Perry AS, Liyanage H, Lawler M and Woodson K: Discovery of DNA hypermethylation using a DHPLC screening strategy. Epigenetics 2: 43-49, 2007. (Pubitemid 46824849)
29. Perry AS, Loftus B, Moroose R, et al: In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer. Br J Cancer 96: 1587-1594, 2007. (Pubitemid 46762961)
30. Endoh H, Yatabe Y, Shimizu S, et al: RASSF1A gene inactivation in non-small cell lung cancer and its clinical implication. Int J Cancer 106: 45-51, 2003. (Pubitemid 36750386)
31. Kuzmin I, Gillespie JW, Protopopov A, et al: The RASSF1A tumor suppressor gene is inactivated in prostate tumors and suppresses growth of prostate carcinoma cells. Cancer Res 62: 3498-3502, 2002. (Pubitemid 34651398)
32. Toyooka S, Pass HI, Shivapurkar N, et al: Aberrant methylation and simian virus 40 tag sequences in malignant mesothelioma. Cancer Res 61: 5727-5730, 2001. (Pubitemid 32769086)
33. Ghoshal K, Datta J, Majumder S, et al: 5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromoadjacent homology domain, and nuclear localization signal. Mol Cell Biol 25: 4727-4741, 2005. (Pubitemid 40705775)
34. Schafer A, Schomacher L, Barreto G, Doderlein G and Niehrs C: Gemcitabine functions epigenetically by inhibiting repair mediated DNA demethylation. PLoS One 5: e14060, 2010.
35. Tsai HC, Li H, Van Neste L, et al: Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21: 430-446, 2012.
36. Ramachandran K, Miller H, Gordian E, Rocha-Lima C and Singal R: Methylation-mediated silencing of TMS1 in pancreatic cancer and its potential contribution to chemosensitivity. Anticancer Res 30: 3919-3925, 2010.
37. de Lange SM, van der Born K, Kroep JR, et al: No evidence of gemcitabine accumulation during weekly administration. Eur J Clin Pharmacol 61: 843-849, 2005.
38. McLaren BR, Robinson BW and Lake RA: New chemotherapeutics in malignant mesothelioma: effects on cell growth and IL-6 production. Cancer Chemother Pharmacol 45: 502-508, 2000. (Pubitemid 30316912)
39. Levenson VV: DNA methylation as a universal biomarker. Expert Rev Mol Diagn 10: 481-488, 2010.
40. Salazar F, Molina MA, Sanchez-Ronco M, et al: First-line therapy and methylation status of CHFR in serum influence outcome to chemotherapy versus EGFR tyrosine kinase inhibitors as second-line therapy in stage IV non-small-cell lung cancer patients. Lung Cancer 72: 84-91, 2011.