Summary
Although the advent of tyrosine kinase inhibitors (TKIs) has dramatically improved the survival of patients with chronic myeloid leukaemia (CML), acquired drug resistance and TKI-insensitive leukaemic stem cells (LSCs) remain major obstacles to a CML cure. In recent years, the reprogramming of mitochondrial metabolism has emerged as a hallmark of cancers, including CML, and in turn may be exploited for therapeutic purposes. Here, we investigated the effects of several drugs on the mitochondrial function of the CML cell line K562 and found that 5-aminoimidazole-4-carboxamide ribotide (AICAR) and decitabine could effectively increase the ATP content and mitochondrial biogenesis. In addition, these two drugs induced cell cycle arrest and a decrease in colony-forming capacity and promoted K562 cell differentiation. Moreover, we demonstrated that treatment with AICAR or decitabine enhanced the sensitivity of K562 cells to imatinib, as evidenced by a combination treatment assay. Altogether, our findings indicate that TKIs combined with mitochondrial regulation may provide a therapeutic strategy for the treatment of CML.
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Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nature Rev, Cancer, 2007,7(6):441–453
Sasaki K, Strom SS, O’Brien S, et al. Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials. Lancet Haematol, 2015,2(5):e186–e193
Bower H, Bjorkholm M, Dickman PW, et al. Life Expectancy of Patients With Chronic Myeloid Leukemia Approaches the Life Expectancy of the General Population. J Clin Oncol, 2016,34(24):2851–2857
Soverini S, Mancini M, Bavaro L, et al. Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy. Mol Cancer, 2018,17(1):49
Chu S, Mcdonald T, Lin A, et al. Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment. Blood, 2011,118(20):5565–5572
Holyoake TL, Vetrie D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood, 2017,129(12):1595–1606
Jain P, Kantarjian HM, Ghorab A, et al. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients. Cancer, 2017,123(22):4391–4402
Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell, 2012,148(6):1145–1159
Tennant DA, Duran RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer, 2010,10(4):267–277
Warburg O. On the origin of cancer cells. Science, 1956,123(3191):309–314
Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell, 2006,9(6):425–434
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 2009,324 (5930):1029–1033
Pavlova NN, Thompson CB. The Emerging Hallmarks of Cancer Metabolism. Cell Metab, 2016,23(1):27–47
Kuntz EM, Baquero P, Michie AM, et al. Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nat Med, 2017,23(10):1234–1240
Gottschalk S, Anderson N, Hainz C, et al. Imatinib (STI571)-mediated changes in glucose metabolism in human leukemia BCR-ABL-positive cells. Clin Cancer Res, 2004,10(19):6661–6668
Horibata S, Vo TV, Subramanian V, et al. Utilization of the Soft Agar Colony Formation Assay to Identify Inhibitors of Tumorigenicity in Breast Cancer Cells. J Vis Exp, 2015(99):e52727
Tsiftsoglou AS, Pappas IS, Vizirianakis IS. Mechanisms involved in the induced differentiation of leukemia cells. Pharmacol Ther, 2003,100(3):257–290
Agathocleous M, Harris WA. Metabolism in physiological cell proliferation and differentiation. Trends Cell Biol, 2013,23(10):484–492
Holyoake TL, Helgason GV. Do we need more drugs for chronic myeloid leukemia? Immunol Rev, 2015,263(1):106–123
Vyas S, Zaganjor E, Haigis MC. Mitochondria and Cancer. Cell, 2016,166(3):555–566
Bogacka I, Xie H, Bray GA, et al. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes, 2005,54(5):1392–1399
Ghosh S, Patel N, Rahn D, et al. The thiazolidinedione pioglitazone alters mitochondrial function in human neuron-like cells. Mol Pharmacol, 2007,71(6):1695–1702
Kukidome D, Nishikawa T, Sonoda K, et al. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes, 2006,55(1):120–127
Noh YH, Kim K, Shim MS, et al.. Inhibition of oxidative stress by coenzyme Q10 increases mitochondrial mass and improves bioenergetic function in optic nerve head astrocytes. Cell Death Dis, 2013,4:e820
Corton JM, Gillespie JG, Hawley SA, et al. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem, 1995,229(2):558–565
Cantó C, Gerhart-Hines Z, Feige JN, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature, 2009,458(7241):1056–1060
Welch JS, Petti AA, Miller CA, et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med, 2016,375(21):2023–2036
Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med, 2001,134(7):573–586
Du L, Yang F, Fang H, et al. AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells. FASEB J, 2019,33(3):4525–4537
Shin DY, Sung Kang H, Kim G, et al. Decitabine, a DNA methyltransferases inhibitor, induces cell cycle arrest at G2/M phase through p53-independent pathway in human cancer cells. Biomed Pharmacother, 2013,67(4):305–311
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The authors declare that there is no conflict of interest with any financial organization or corporation or individual that can inappropriately influence this work.
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Zhu, Xy., Liu, W., Liang, Ht. et al. AICAR and Decitabine Enhance the Sensitivity of K562 Cells to Imatinib by Promoting Mitochondrial Activity. CURR MED SCI 40, 871–878 (2020). https://doi.org/10.1007/s11596-020-2266-1
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DOI: https://doi.org/10.1007/s11596-020-2266-1