Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target
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- 作者：Kongfei Li ; Chao Hu ; Chen Mei ; Zhigang Ren…
- 关键词：Decitabine ; Idarubicin ; Wnt ; Acute myeloid leukemia ; Myelodysplastic syndromes
- 刊名：Journal of Translational Medicine
- 出版年：2014
- 出版时间：December 2014
- 年：2014
- 卷：12
- 期：1
- 全文大小：2,836 KB
- 参考文献：1. Jones, PA, Taylor, SM (1980) Cellular differentiation, cytidine analogs and DNA methylation. Cell 20: pp. 85-93 CrossRef
2. Toyota, M, Kopecky, KJ, Toyota, MO, Jair, KW, Willman, CL, Issa, JP (2001) Methylation profiling in acute myeloid leukemia. Blood 97: pp. 2823-2829 CrossRef
3. Santi, DV, Norment, A, Garrett, CE (1984) Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. Proc Natl Acad Sci U S A 81: pp. 6993-6997 CrossRef
4. Qin, T, Youssef, EM, Jelinek, J, Chen, R, Yang, AS, Garcia-Manero, G, Issa, JP (2007) Effect of cytarabine and decitabine in combination in human leukemic cell lines. Clin Cancer Res 13: pp. 4225-4232 CrossRef
5. Creusot, F, Acs, G, Christman, JK (1982) Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2-deoxycytidine. J Biol Chem 257: pp. 2041-2048
6. Yang, AS, Doshi, KD, Choi, SW, Mason, JB, Mannari, RK, Gharybian, V, Luna, R, Rashid, A, Shen, L, Estecio, MR, Kantarjian, HM, Garcia-Manero, G, Issa, JP (2006) DNA methylation changes after 5-aza-2-deoxycytidine therapy in patients with leukemia. Cancer Res 66: pp. 5495-5503 CrossRef
7. Kantarjian, H, Issa, JP, Rosenfeld, CS, Bennett, JM, Albitar, M, DiPersio, J, Klimek, V, Slack, J, de Castro, C, Ravandi, F, Helmer, R, Shen, L, Nimer, SD, Leavitt, R, Raza, A, Saba, H (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106: pp. 1794-1803 CrossRef
8. Issa, JP, Garcia-Manero, G, Giles, FJ, Mannari, R, Thomas, D, Faderl, S, Bayar, E, Lyons, J, Rosenfeld, CS, Cortes, J, Kantarjian, HM (2004) Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 103: pp. 1635-1640 CrossRef
9. Gore, SD, Baylin, S, Sugar, E, Carraway, H, Miller, CB, Carducci, M, Grever, M, Galm, O, Dauses, T, Karp, JE, Rudek, MA, Zhao, M, Smith, BD, Manning, J, Jiemjit, A, Dover, G, Mays, A, Zwiebel, J, Murgo, A, Weng, LJ, Herman, JG (2006) Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66: pp. 6361-6369 CrossRef
10. Blum, W, Klisovic, RB, Hackanson, B, Liu, Z, Liu, S, Devine, H, Vukosavljevic, T, Huynh, L, Lozanski, G, Kefauver, C, Plass, C, Devine, SM, Heerema, NA, Murgo, A, Chan, KK, Grever, MR, Byrd, JC, Marcucci, G (2007) Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 25: pp. 3884-3891 CrossRef
11. Sundstrom, C, Nilsson, K (1976) Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer 17: pp. 565-577 CrossRef
12. Martin, P, Papayannopoulou, T (1982) HEL cells: a new human erythroleukemia cell line with spontaneous and induced globin expression. Science 216: pp. 1233-1235 CrossRef
13. Nakagawa, T, Matozaki, S (1995) The SKM-1 leukemic cell line established from a patient with progression to myelomonocytic leukemia in myelodysplastic syndrome (MDS)-contribution to better understanding of MDS. Leuk Lymphoma 17: pp. 335-339 CrossRef
14. Griffiths, EA, Gore, SD, Hooker, C, McDevitt, MA, Karp, JE, Smith, BD, Mohammad, HP, Ye, Y, Herman, JG, Carraway, HE (2010) Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation. Leuk Lymphoma 51: pp. 1711-1719
文摘
Background The methylation inhibitor 5-Aza-2-deoxycytidine (decitabine, DAC) has a great therapeutic value for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). But decitabine monotherapy was associated with a relatively low rate of complete remission in AML and MDS. We aimed to investigate the effect of several anti-leukemia drugs in combination with decitabine on the proliferation of myeloid leukemia cells, to select the most efficient combination group and explore the associated mechanisms of these combination therapies. Methods Cell proliferation was tested by MTT assay and CFU-GM assay. Cell apoptosis was evaluated by Annexin V and PI staining in cell culture, TUNEL assay and transmission electron microscopy in animal study. MicroPET was used to imaging the tumor in mouse model. Molecular studies were conducted using microarray expression analysis, which was used to explore associated pathways, and real-time quantitative reverse transcription-PCR, western blot and immunohistochemistry, used to assess regulation of Wnt/β-catenin pathway. Statistical significance among groups was determined by one-way ANOVA analysis followed by post hoc Bonferroni’s multiple comparison test. Results Among five anti-leukemia agents in combining with decitabine, the sequential combination of decitabine and idarubicin induced synergistic cell death in U937 cells, and this effect was verified in HEL, SKM-1 cells and AML cells isolated from AML patients. Importantly, tumor growth inhibition in this sequential combination was found to be higher than in single agent or controls in vivo. Moreover, sequential combination of the two agents induced apoptosis and depression of the Wnt/β-catenin pathway in both AML cell culture and animal studies. Conclusions The findings demonstrated that sequentially combination of decitabine and idarubicin had synergistic anti-leukemia effects. These effects were mainly attributed to demethylation of Wnt/β-catenin pathway inhibitors and downregulation of Wnt/β-catenin pathway nuclear targets.