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Current Medicinal Chemistry

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ISSN (Online): 1875-533X

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Review Article

The Role of AMPK/mTOR Modulators in the Therapy of Acute Myeloid Leukemia

Author(s): Dora Visnjic*, Vilma Dembitz and Hrvoje Lalic

Volume 26, Issue 12, 2019

Page: [2208 - 2229] Pages: 22

DOI: 10.2174/0929867325666180117105522

Price: $65

Abstract

Differentiation therapy of acute promyelocytic leukemia with all-trans retinoic acid represents the most successful pharmacological therapy of acute myeloid leukemia (AML). Numerous studies demonstrate that drugs that inhibit mechanistic target of rapamycin (mTOR) and activate AMP-kinase (AMPK) have beneficial effects in promoting differentiation and blocking proliferation of AML. Most of these drugs are already in use for other purposes; rapalogs as immunosuppressants, biguanides as oral antidiabetics, and 5-amino-4-imidazolecarboxamide ribonucleoside (AICAr, acadesine) as an exercise mimetic. Although most of these pharmacological modulators have been widely used for decades, their mechanism of action is only partially understood. In this review, we summarize the role of AMPK and mTOR in hematological malignancies and discuss the possible role of pharmacological modulators in proliferation and differentiation of leukemia cells.

Keywords: AML, AMPK, mTOR, rapamycin, metformin, AICAR, differentiation.

« Previous
[1]
Khwaja, A.; Bjorkholm, M.; Gale, R.E.; Levine, R.L.; Jordan, C.T.; Ehninger, G.; Bloomfield, C.D.; Estey, E.; Burnett, A.; Cornelissen, J.J.; Scheinberg, D.A.; Bouscary, D.; Linch, D.C. Acute myeloid leukaemia. Nat. Rev. Dis. Primers, 2016, 2, 16010.
[http://dx.doi.org/10.1038/nrdp.2016.10] [PMID: 27159408]
[2]
De Kouchkovsky, I.; Abdul-Hay, M. ‘Acute myeloid leukemia: a comprehensive review and 2016 update’. Blood Cancer J., 2016, 6(7), e441.
[http://dx.doi.org/10.1038/bcj.2016.50] [PMID: 27367478]
[3]
Coombs, C.C.; Tavakkoli, M.; Tallman, M.S. Acute promyelocytic leukemia: where did we start, where are we now, and the future. Blood Cancer J., 2015. 5e304
[4]
Lo-Coco, F.; Avvisati, G.; Vignetti, M.; Thiede, C.; Orlando, S.M.; Iacobelli, S.; Ferrara, F.; Fazi, P.; Cicconi, L.; Di Bona, E.; Specchia, G.; Sica, S.; Divona, M.; Levis, A.; Fiedler, W.; Cerqui, E.; Breccia, M.; Fioritoni, G.; Salih, H.R.; Cazzola, M.; Melillo, L.; Carella, A.M.; Brandts, C.H.; Morra, E.; von Lilienfeld-Toal, M.; Hertenstein, B.; Wattad, M.; Lübbert, M.; Hänel, M.; Schmitz, N.; Link, H.; Kropp, M.G.; Rambaldi, A.; La Nasa, G.; Luppi, M.; Ciceri, F.; Finizio, O.; Venditti, A.; Fabbiano, F.; Döhner, K.; Sauer, M.; Ganser, A.; Amadori, S.; Mandelli, F.; Döhner, H.; Ehninger, G.; Schlenk, R.F.; Platzbecker, U. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med., 2013, 369(2), 111-121.
[http://dx.doi.org/10.1056/NEJMoa1300874] [PMID: 23841729]
[5]
van Gils, N.; Verhagen, H.J.M.P.; Smit, L. Reprogramming acute myeloid leukemia into sensitivity for retinoic-acid-driven differentiation. Exp. Hematol., 2017, 52, 12-23.
[http://dx.doi.org/10.1016/j.exphem.2017.04.007] [PMID: 28456748]
[6]
Breitman, T.R.; Selonick, S.E.; Collins, S.J. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc. Natl. Acad. Sci. USA, 1980, 77(5), 2936-2940.
[http://dx.doi.org/10.1073/pnas.77.5.2936] [PMID: 6930676]
[7]
Petrie, K.; Zelent, A.; Waxman, S. Differentiation therapy of acute myeloid leukemia: past, present and future. Curr. Opin. Hematol., 2009, 16(2), 84-91.
[http://dx.doi.org/10.1097/MOH.0b013e3283257aee] [PMID: 19468269]
[8]
Martelli, A.M.; Evangelisti, C.; Follo, M.Y.; Ramazzotti, G.; Fini, M.; Giardino, R.; Manzoli, L.; McCubrey, J.A.; Cocco, L. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cells. Curr. Med. Chem., 2011, 18(18), 2715-2726.
[http://dx.doi.org/10.2174/092986711796011201] [PMID: 21649579]
[9]
Matkovic, K.; Brugnoli, F.; Bertagnolo, V.; Banfic, H.; Visnjic, D. The role of the nuclear Akt activation and Akt inhibitors in all-trans-retinoic acid-differentiated HL-60 cells. Leukemia, 2006, 20(6), 941-951.
[http://dx.doi.org/10.1038/sj.leu.2404204] [PMID: 16617325]
[10]
Mise, J.; Dembitz, V.; Banfic, H.; Visnjic, D. Combined inhibition of PI3K and mTOR exerts synergistic antiproliferative effect, but diminishes differentiative properties of rapamycin in acute myeloid leukemia cells. Pathol. Oncol. Res., 2011, 17(3), 645-656.
[http://dx.doi.org/10.1007/s12253-011-9365-z] [PMID: 21336564]
[11]
Nishioka, C.; Ikezoe, T.; Yang, J.; Gery, S.; Koeffler, H.P.; Yokoyama, A. Inhibition of mammalian target of rapamycin signaling potentiates the effects of all-trans retinoic acid to induce growth arrest and differentiation of human acute myelogenous leukemia cells. Int. J. Cancer, 2009, 125(7), 1710-1720.
[http://dx.doi.org/10.1002/ijc.24472] [PMID: 19507250]
[12]
Lalic, H.; Lukinovic-Skudar, V.; Banfic, H.; Visnjic, D. Rapamycin enhances dimethyl sulfoxide-mediated growth arrest in human myelogenous leukemia cells. Leuk. Lymphoma, 2012, 53(11), 2253-2261.
[http://dx.doi.org/10.3109/10428194.2012.684351] [PMID: 22497230]
[13]
Hardie, D.G. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev., 2011, 25(18), 1895-1908.
[http://dx.doi.org/10.1101/gad.17420111] [PMID: 21937710]
[14]
Lalic, H.; Dembitz, V.; Lukinovic-Skudar, V.; Banfic, H.; Visnjic, D. 5-Aminoimidazole-4-carboxamide ribonucleoside induces differentiation of acute myeloid leukemia cells. Leuk. Lymphoma, 2014, 55(10), 2375-2383.
[http://dx.doi.org/10.3109/10428194.2013.876633] [PMID: 24359245]
[15]
Hauge, M.; Bruserud, Ø.; Hatfield, K.J. Targeting of cell metabolism in human acute myeloid leukemia--more than targeting of isocitrate dehydrogenase mutations and PI3K/AKT/mTOR signaling? Eur. J. Haematol., 2016, 96(3), 211-221.
[http://dx.doi.org/10.1111/ejh.12690] [PMID: 26465810]
[16]
Sehgal, S.N. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant. Proc., 2003, 35(3)(Suppl.), 7S-14S.
[http://dx.doi.org/10.1016/S0041-1345(03)00211-2] [PMID: 12742462]
[17]
Heitman, J.; Movva, N.R.; Hall, M.N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science, 1991, 253(5022), 905-909.
[http://dx.doi.org/10.1126/science.1715094] [PMID: 1715094]
[18]
Saxton, R.A.; Sabatini, D.M. mTOR signaling in growth; metabolism; and disease. Cell, 2017, 168(6), 960-976.
[http://dx.doi.org/10.1016/j.cell.2017.02.004] [PMID: 28283069]
[19]
Yu, J.S.L.; Cui, W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development, 2016, 143(17), 3050-3060.
[http://dx.doi.org/10.1242/dev.137075] [PMID: 27578176]
[20]
Kennedy, B.K.; Lamming, D.W. The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging. Cell Metab., 2016, 23(6), 990-1003.
[http://dx.doi.org/10.1016/j.cmet.2016.05.009] [PMID: 27304501]
[21]
Laplante, M.; Sabatini, D.M. mTOR signaling in growth control and disease. Cell, 2012, 149(2), 274-293.
[http://dx.doi.org/10.1016/j.cell.2012.03.017] [PMID: 22500797]
[22]
Chiarini, F.; Evangelisti, C.; McCubrey, J.A.; Martelli, A.M. Current treatment strategies for inhibiting mTOR in cancer. Trends Pharmacol. Sci., 2015, 36(2), 124-135.
[http://dx.doi.org/10.1016/j.tips.2014.11.004] [PMID: 25497227]
[23]
Grabiner, B.C.; Nardi, V.; Birsoy, K.; Possemato, R.; Shen, K.; Sinha, S.; Jordan, A.; Beck, A.H.; Sabatini, D.M. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov., 2014, 4(5), 554-563.
[http://dx.doi.org/10.1158/2159-8290.CD-13-0929] [PMID: 24631838]
[24]
Xu, Q.; Simpson, S.E.; Scialla, T.J.; Bagg, A.; Carroll, M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood, 2003, 102(3), 972-980.
[http://dx.doi.org/10.1182/blood-2002-11-3429] [PMID: 12702506]
[25]
Min, Y.H.; Eom, J.I.; Cheong, J.W.; Maeng, H.O.; Kim, J.Y.; Jeung, H.K.; Lee, S.T.; Lee, M.H.; Hahn, J.S.; Ko, Y.W. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia, 2003, 17(5), 995-997.
[http://dx.doi.org/10.1038/sj.leu.2402874] [PMID: 12750723]
[26]
Kubota, Y.; Ohnishi, H.; Kitanaka, A.; Ishida, T.; Tanaka, T. Constitutive activation of PI3K is involved in the spontaneous proliferation of primary acute myeloid leukemia cells: direct evidence of PI3K activation. Leukemia, 2004, 18(8), 1438-1440.
[http://dx.doi.org/10.1038/sj.leu.2403402] [PMID: 15175626]
[27]
Grandage, V.L.; Gale, R.E.; Linch, D.C.; Khwaja, A. PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways. Leukemia, 2005, 19(4), 586-594.
[http://dx.doi.org/10.1038/sj.leu.2403653] [PMID: 15703783]
[28]
Récher, C.; Beyne-Rauzy, O.; Demur, C.; Chicanne, G.; Dos Santos, C.; Mas, V.M.; Benzaquen, D.; Laurent, G.; Huguet, F.; Payrastre, B. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood, 2005, 105(6), 2527-2534.
[http://dx.doi.org/10.1182/blood-2004-06-2494] [PMID: 15550488]
[29]
Dinner, S.; Platanias, L.C. Targeting mTOR pathway in leukemia. J. Cell. Biochem., 2016, 117(8), 1745-1752.
[http://dx.doi.org/10.1002/jcb.25559] [PMID: 27018341]
[30]
Tabe, Y.; Tafuri, A.; Sekihara, K.; Yang, H.; Konopleva, M. Inhibition of mTOR kinase as a therapeutic target for acute myeloid leukemia. Expert Opin. Ther. Targets, 2017, 21(7), 705-714.
[http://dx.doi.org/10.1080/14728222.2017.1333600] [PMID: 28537457]
[31]
Herschbein, L.; Liesveld, J.L. Dueling for dual inhibition: Means to enhance effectiveness of PI3K/Akt/mTOR inhibitors in AML. Blood Rev., 2018, 2(3), 235-248.
[http://dx.doi.org/10.1016/j.blre.2017.11.006] [PMID: 29276026]
[32]
Konopleva, M.Y.; Walter, R.B.; Faderl, S.H.; Jabbour, E.J.; Zeng, Z.; Borthakur, G.; Huang, X.; Kadia, T.M.; Ruvolo, P.P.; Feliu, J.B.; Lu, H.; Debose, L.; Burger, J.A.; Andreeff, M.; Liu, W.; Baggerly, K.A.; Kornblau, S.M.; Doyle, L.A.; Estey, E.H.; Kantarjian, H.M. Preclinical and early clinical evaluation of the oral AKT inhibitor, MK-2206, for the treatment of acute myelogenous leukemia. Clin. Cancer Res., 2014, 20(8), 2226-2235.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-1978] [PMID: 24583795]
[33]
Gojo, I.; Perl, A.; Luger, S.; Baer, M.R.; Norsworthy, K.J.; Bauer, K.S.; Tidwell, M.; Fleckinger, S.; Carroll, M.; Sausville, E.A. Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome. Invest. New Drugs, 2013, 31(5), 1217-1227.
[http://dx.doi.org/10.1007/s10637-013-9937-8] [PMID: 23443507]
[34]
Ragon, B.K.; Kantarjian, H.; Jabbour, E.; Ravandi, F.; Cortes, J.; Borthakur, G.; DeBose, L.; Zeng, Z.; Schneider, H.; Pemmaraju, N.; Garcia-Manero, G.; Kornblau, S.; Wierda, W.; Burger, J.; DiNardo, C.D.; Andreeff, M.; Konopleva, M.; Daver, N. Buparlisib, a PI3K inhibitor, demonstrates acceptable tolerability and preliminary activity in a phase I trial of patients with advanced leukemias. Am. J. Hematol., 2017, 92(1), 7-11.
[http://dx.doi.org/10.1002/ajh.24568] [PMID: 27673440]
[35]
Dos Santos, C.; Demur, C.; Bardet, V.; Prade-Houdellier, N.; Payrastre, B.; Récher, C. A critical role for Lyn in acute myeloid leukemia. Blood, 2008, 111(4), 2269-2279.
[http://dx.doi.org/10.1182/blood-2007-04-082099] [PMID: 18056483]
[36]
Kalaitzidis, D.; Sykes, S.M.; Wang, Z.; Punt, N.; Tang, Y.; Ragu, C.; Sinha, A.U.; Lane, S.W.; Souza, A.L.; Clish, C.B.; Anastasiou, D.; Gilliland, D.G.; Scadden, D.T.; Guertin, D.A.; Armstrong, S.A. mTOR complex 1 plays critical roles in hematopoiesis and Pten-loss-evoked leukemogenesis. Cell Stem Cell, 2012, 11(3), 429-439.
[http://dx.doi.org/10.1016/j.stem.2012.06.009] [PMID: 22958934]
[37]
Hoshii, T.; Tadokoro, Y.; Naka, K.; Ooshio, T.; Muraguchi, T.; Sugiyama, N.; Soga, T.; Araki, K.; Yamamura, K.; Hirao, A. mTORC1 is essential for leukemia propagation but not stem cell self-renewal. J. Clin. Invest., 2012, 122(6), 2114-2129.
[http://dx.doi.org/10.1172/JCI62279] [PMID: 22622041]
[38]
Ghosh, J.; Kobayashi, M.; Ramdas, B.; Chatterjee, A.; Ma, P.; Mali, R.S.; Carlesso, N.; Liu, Y.; Plas, D.R.; Chan, R.J.; Kapur, R. S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance. J. Clin. Invest., 2016, 126(7), 2621-2625.
[http://dx.doi.org/10.1172/JCI84565] [PMID: 27294524]
[39]
Gao, Y.; Gao, J.; Li, M.; Zheng, Y.; Wang, Y.; Zhang, H.; Wang, W.; Chu, Y.; Wang, X.; Xu, M.; Cheng, T.; Ju, Z.; Yuan, W. Rheb1 promotes tumor progression through mTORC1 in MLL-AF9-initiated murine acute myeloid leukemia. J. Hematol. Oncol., 2016, 9, 36.
[http://dx.doi.org/10.1186/s13045-016-0264-3] [PMID: 27071307]
[40]
U.S. Food and Drug Administration. www.fda.gov
[41]
Li, J.; Kim, S.G.; Blenis, J. Rapamycin: one drug, many effects. Cell Metab., 2014, 19(3), 373-379.
[http://dx.doi.org/10.1016/j.cmet.2014.01.001] [PMID: 24508508]
[42]
Pollizzi, K.N.; Powell, J.D. Regulation of T cells by mTOR: the known knowns and the known unknowns. Trends Immunol., 2015, 36(1), 13-20.
[http://dx.doi.org/10.1016/j.it.2014.11.005] [PMID: 25522665]
[43]
Fantus, D.; Thomson, A.W. Evolving perspectives of mTOR complexes in immunity and transplantation. Am. J. Transplant., 2015, 15(4), 891-902.
[http://dx.doi.org/10.1111/ajt.13151] [PMID: 25737114]
[44]
Eng, C.P.; Sehgal, S.N.; Vézina, C. Activity of rapamycin (AY-22,989) against transplanted tumors. J. Antibiot. (Tokyo), 1984, 37(10), 1231-1237.
[http://dx.doi.org/10.7164/antibiotics.37.1231] [PMID: 6501094]
[45]
Price, D.J.; Grove, J.R.; Calvo, V.; Avruch, J.; Bierer, B.E. Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science, 1992, 257(5072), 973-977.
[http://dx.doi.org/10.1126/science.1380182] [PMID: 1380182]
[46]
Muthukkumar, S.; Ramesh, T.M.; Bondada, S. Rapamycin, a potent immunosuppressive drug, causes programmed cell death in B lymphoma cells. Transplantation, 1995, 60(3), 264-270.
[http://dx.doi.org/10.1097/00007890-199508000-00010] [PMID: 7544036]
[47]
Brown, V.I.; Fang, J.; Alcorn, K.; Barr, R.; Kim, J.M.; Wasserman, R.; Grupp, S.A. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc. Natl. Acad. Sci. USA, 2003, 100(25), 15113-15118.
[http://dx.doi.org/10.1073/pnas.2436348100] [PMID: 14657335]
[48]
Avellino, R.; Romano, S.; Parasole, R.; Bisogni, R.; Lamberti, A.; Poggi, V.; Venuta, S.; Romano, M.F. Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood, 2005, 106(4), 1400-1406.
[http://dx.doi.org/10.1182/blood-2005-03-0929] [PMID: 15878982]
[49]
Mohi, M.G.; Boulton, C.; Gu, T.L.; Sternberg, D.W.; Neuberg, D.; Griffin, J.D.; Gilliland, D.G.; Neel, B.G. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc. Natl. Acad. Sci. USA, 2004, 101(9), 3130-3135.
[http://dx.doi.org/10.1073/pnas.0400063101] [PMID: 14976243]
[50]
Xu, Q.; Thompson, J.E.; Carroll, M. mTOR regulates cell survival after etoposide treatment in primary AML cells. Blood, 2005, 106(13), 4261-4268.
[http://dx.doi.org/10.1182/blood-2004-11-4468] [PMID: 16150937]
[51]
Rizzieri, D.A.; Feldman, E.; Dipersio, J.F.; Gabrail, N.; Stock, W.; Strair, R.; Rivera, V.M.; Albitar, M.; Bedrosian, C.L.; Giles, F.J. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin. Cancer Res., 2008, 14(9), 2756-2762.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-1372] [PMID: 18451242]
[52]
Yee, K.W.; Zeng, Z.; Konopleva, M.; Verstovsek, S.; Ravandi, F.; Ferrajoli, A.; Thomas, D.; Wierda, W.; Apostolidou, E.; Albitar, M.; O’Brien, S.; Andreeff, M.; Giles, F.J. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin. Cancer Res., 2006, 12(17), 5165-5173.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-0764] [PMID: 16951235]
[53]
Perl, A.E.; Kasner, M.T.; Tsai, D.E.; Vogl, D.T.; Loren, A.W.; Schuster, S.J.; Porter, D.L.; Stadtmauer, E.A.; Goldstein, S.C.; Frey, N.V.; Nasta, S.D.; Hexner, E.O.; Dierov, J.K.; Swider, C.R.; Bagg, A.; Gewirtz, A.M.; Carroll, M.; Luger, S.M. A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia. Clin. Cancer Res., 2009, 15(21), 6732-6739.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-0842] [PMID: 19843663]
[54]
Amadori, S.; Stasi, R.; Martelli, A.M.; Venditti, A.; Meloni, G.; Pane, F.; Martinelli, G.; Lunghi, M.; Pagano, L.; Cilloni, D.; Rossetti, E.; Di Raimondo, F.; Fozza, C.; Annino, L.; Chiarini, F.; Ricci, F.; Ammatuna, E.; La Sala, E.; Fazi, P.; Vignetti, M. Temsirolimus, an mTOR inhibitor, in combination with lower-dose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107). Br. J. Haematol., 2012, 156(2), 205-212.
[http://dx.doi.org/10.1111/j.1365-2141.2011.08940.x] [PMID: 22082314]
[55]
Park, S.; Chapuis, N.; Saint Marcoux, F.; Recher, C.; Prebet, T.; Chevallier, P.; Cahn, J.Y.; Leguay, T.; Bories, P.; Witz, F.; Lamy, T.; Mayeux, P.; Lacombe, C.; Demur, C.; Tamburini, J.; Merlat, A.; Delepine, R.; Vey, N.; Dreyfus, F.; Béné, M.C.; Ifrah, N.; Bouscary, D. A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse. Leukemia, 2013, 27(7), 1479-1486.
[http://dx.doi.org/10.1038/leu.2013.17] [PMID: 23321953]
[56]
Calimeri, T.; Ferreri, A.J.M. m-TOR inhibitors and their potential role in haematological malignancies. Br. J. Haematol., 2017, 177(5), 684-702.
[http://dx.doi.org/10.1111/bjh.14529] [PMID: 28146265]
[57]
Bertagnolo, V.; Neri, L.M.; Marchisio, M.; Mischiati, C.; Capitani, S. Phosphoinositide 3-kinase activity is essential for all-trans-retinoic acid-induced granulocytic differentiation of HL-60 cells. Cancer Res., 1999, 59(3), 542-546.
[PMID: 9973197]
[58]
Sykes, S.M.; Lane, S.W.; Bullinger, L.; Kalaitzidis, D.; Yusuf, R.; Saez, B.; Ferraro, F.; Mercier, F.; Singh, H.; Brumme, K.M.; Acharya, S.S.; Scholl, C.; Tothova, Z.; Attar, E.C.; Fröhling, S.; DePinho, R.A.; Armstrong, S.A.; Gilliland, D.G.; Scadden, D.T. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell, 2011, 146(5), 697-708.
[http://dx.doi.org/10.1016/j.cell.2011.07.032] [PMID: 21884932]
[59]
Jayaraman, T.; Marks, A.R. Rapamycin-FKBP12 blocks proliferation, induces differentiation, and inhibits cdc2 kinase activity in a myogenic cell line. J. Biol. Chem., 1993, 268(34), 25385-25388.
[PMID: 7503980]
[60]
Buscà, R.; Bertolotto, C.; Ortonne, J.P.; Ballotti, R. Inhibition of the phosphatidylinositol 3-kinase/p70(S6)-kinase pathway induces B16 melanoma cell differentiation. J. Biol. Chem., 1996, 271(50), 31824-31830.
[http://dx.doi.org/10.1074/jbc.271.50.31824] [PMID: 8943224]
[61]
Ogawa, T.; Tokuda, M.; Tomizawa, K.; Matsui, H.; Itano, T.; Konishi, R.; Nagahata, S.; Hatase, O. Osteoblastic differentiation is enhanced by rapamycin in rat osteoblast-like osteosarcoma (ROS 17/2.8) cells. Biochem. Biophys. Res. Commun., 1998, 249(1), 226-230.
[http://dx.doi.org/10.1006/bbrc.1998.9118] [PMID: 9705862]
[62]
Yamamoto-Yamaguchi, Y.; Okabe-Kado, J.; Kasukabe, T.; Honma, Y. Induction of differentiation of human myeloid leukemia cells by immunosuppressant macrolides (rapamycin and FK506) and calcium/calmodulin-dependent kinase inhibitors. Exp. Hematol., 2001, 29(5), 582-588.
[http://dx.doi.org/10.1016/S0301-472X(01)00626-9] [PMID: 11376870]
[63]
Nishioka, C.; Ikezoe, T.; Yang, J.; Koeffler, H.P.; Yokoyama, A. Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells. Leukemia, 2008, 22(12), 2159-2168.
[http://dx.doi.org/10.1038/leu.2008.243] [PMID: 18784743]
[64]
Gadhoum, S.Z.; Madhoun, N.Y.; Abuelela, A.F.; Merzaban, J.S. Anti-CD44 antibodies inhibit both mTORC1 and mTORC2: a new rationale supporting CD44-induced AML differentiation therapy. Leukemia, 2016, 30(12), 2397-2401.
[http://dx.doi.org/10.1038/leu.2016.221] [PMID: 27499140]
[65]
Yang, J.; Ikezoe, T.; Nishioka, C.; Ni, L.; Koeffler, H.P.; Yokoyama, A. Inhibition of mTORC1 by RAD001 (everolimus) potentiates the effects of 1,25-dihydroxyvitamin D(3) to induce growth arrest and differentiation of AML cells in vitro and in vivo. Exp. Hematol., 2010, 38(8), 666-676.
[http://dx.doi.org/10.1016/j.exphem.2010.03.020] [PMID: 20382200]
[66]
Dembitz, V.; Lalic, H.; Ostojic, A.; Vrhovac, R.; Banfic, H.; Visnjic, D. The mechanism of synergistic effects of arsenic trioxide and rapamycin in acute myeloid leukemia cell lines lacking typical t(15;17) translocation. Int. J. Hematol., 2015, 102(1), 12-24.
[http://dx.doi.org/10.1007/s12185-015-1776-2] [PMID: 25758096]
[67]
Isakson, P.; Bjørås, M.; Bøe, S.O.; Simonsen, A. Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein. Blood, 2010, 116(13), 2324-2331.
[http://dx.doi.org/10.1182/blood-2010-01-261040] [PMID: 20574048]
[68]
Neri, L.M.; Marchisio, M.; Colamussi, M.L.; Bertagnolo, V. Monocytic differentiation of HL-60 cells is characterized by the nuclear translocation of phosphatidylinositol 3-kinase and of definite phosphatidylinositol-specific phospholipase C isoforms. Biochem. Biophys. Res. Commun., 1999, 259(2), 314-320.
[http://dx.doi.org/10.1006/bbrc.1999.0786] [PMID: 10362505]
[69]
Zhang, Y.; Zhang, J.; Studzinski, G.P. AKT pathway is activated by 1, 25-dihydroxyvitamin D3 and participates in its anti-apoptotic effect and cell cycle control in differentiating HL60 cells. Cell Cycle, 2006, 5(4), 447-451.
[http://dx.doi.org/10.4161/cc.5.4.2467] [PMID: 16479173]
[70]
Carling, D.; Clarke, P.R.; Zammit, V.A.; Hardie, D.G. Purification and characterization of the AMP-activated protein kinase. Copurification of acetyl-CoA carboxylase kinase and 3-hydroxy-3-methylglutaryl-CoA reductase kinase activities. Eur. J. Biochem., 1989, 186(1-2), 129-136.
[http://dx.doi.org/10.1111/j.1432-1033.1989.tb15186.x] [PMID: 2598924]
[71]
Carling, D. AMPK signalling in health and disease. Curr. Opin. Cell Biol., 2017, 45, 31-37.
[http://dx.doi.org/10.1016/j.ceb.2017.01.005] [PMID: 28232179]
[72]
Garcia, D.; Shaw, R.J. AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. Mol. Cell, 2017, 66(6), 789-800.
[http://dx.doi.org/10.1016/j.molcel.2017.05.032] [PMID: 28622524]
[73]
Dasgupta, B.; Chhipa, R.R. Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer. Trends Pharmacol. Sci., 2016, 37(3), 192-206.
[http://dx.doi.org/10.1016/j.tips.2015.11.007] [PMID: 26711141]
[74]
Hardie, D.G. AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes, 2013, 62(7), 2164-2172.
[http://dx.doi.org/10.2337/db13-0368] [PMID: 23801715]
[75]
Hardie, D.G. AMPK--sensing energy while talking to other signaling pathways. Cell Metab., 2014, 20(6), 939-952.
[http://dx.doi.org/10.1016/j.cmet.2014.09.013] [PMID: 25448702]
[76]
Hardie, D.G. Molecular Pathways: Is AMPK a Friend or a Foe in Cancer? Clin. Cancer Res., 2015, 21(17), 3836-3840.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-3300] [PMID: 26152739]
[77]
Hawley, S.A.; Ross, F.A.; Chevtzoff, C.; Green, K.A.; Evans, A.; Fogarty, S.; Towler, M.C.; Brown, L.J.; Ogunbayo, O.A.; Evans, A.M.; Hardie, D.G. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab., 2010, 11(6), 554-565.
[http://dx.doi.org/10.1016/j.cmet.2010.04.001] [PMID: 20519126]
[78]
Liu, X.; Chhipa, R.R.; Pooya, S.; Wortman, M.; Yachyshin, S.; Chow, L.M.; Kumar, A.; Zhou, X.; Sun, Y.; Quinn, B.; McPherson, C.; Warnick, R.E.; Kendler, A.; Giri, S.; Poels, J.; Norga, K.; Viollet, B.; Grabowski, G.A.; Dasgupta, B. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc. Natl. Acad. Sci. USA, 2014, 111(4), E435-E444.
[http://dx.doi.org/10.1073/pnas.1311121111] [PMID: 24474794]
[79]
Vincent, E.E.; Coelho, P.P.; Blagih, J.; Griss, T.; Viollet, B.; Jones, R.G. Differential effects of AMPK agonists on cell growth and metabolism. Oncogene, 2015, 34(28), 3627-3639.
[http://dx.doi.org/10.1038/onc.2014.301] [PMID: 25241895]
[80]
O’Neill, H.M.; Maarbjerg, S.J.; Crane, J.D.; Jeppesen, J.; Jørgensen, S.B.; Schertzer, J.D.; Shyroka, O.; Kiens, B.; van Denderen, B.J.; Tarnopolsky, M.A.; Kemp, B.E.; Richter, E.A.; Steinberg, G.R. AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc. Natl. Acad. Sci. USA, 2011, 108(38), 16092-16097.
[http://dx.doi.org/10.1073/pnas.1105062108] [PMID: 21896769]
[81]
Sakamoto, K.; McCarthy, A.; Smith, D.; Green, K.A.; Grahame Hardie, D.; Ashworth, A.; Alessi, D.R. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J., 2005, 24(10), 1810-1820.
[http://dx.doi.org/10.1038/sj.emboj.7600667] [PMID: 15889149]
[82]
Sung, M.M.; Zordoky, B.N.; Bujak, A.L.; Lally, J.S.; Fung, D.; Young, M.E.; Horman, S.; Miller, E.J.; Light, P.E.; Kemp, B.E.; Steinberg, G.R.; Dyck, J.R. AMPK deficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism. Cardiovasc. Res., 2015, 107(2), 235-245.
[http://dx.doi.org/10.1093/cvr/cvv166] [PMID: 26023060]
[83]
Jessen, N.; Koh, H.J.; Folmes, C.D.; Wagg, C.; Fujii, N.; Løfgren, B.; Wolf, C.M.; Berul, C.I.; Hirshman, M.F.; Lopaschuk, G.D.; Goodyear, L.J. Ablation of LKB1 in the heart leads to energy deprivation and impaired cardiac function. Biochim. Biophys. Acta, 2010, 1802(7-8), 593-600.
[http://dx.doi.org/10.1016/j.bbadis.2010.04.008] [PMID: 20441792]
[84]
Russell, R.R., III; Li, J.; Coven, D.L.; Pypaert, M.; Zechner, C.; Palmeri, M.; Giordano, F.J.; Mu, J.; Birnbaum, M.J.; Young, L.H. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J. Clin. Invest., 2004, 114(4), 495-503.
[http://dx.doi.org/10.1172/JCI19297] [PMID: 15314686]
[85]
Shaw, R.J.; Lamia, K.A.; Vasquez, D.; Koo, S.H.; Bardeesy, N.; Depinho, R.A.; Montminy, M.; Cantley, L.C. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science, 2005, 310(5754), 1642-1646.
[http://dx.doi.org/10.1126/science.1120781] [PMID: 16308421]
[86]
Foretz, M.; Hébrard, S.; Leclerc, J.; Zarrinpashneh, E.; Soty, M.; Mithieux, G.; Sakamoto, K.; Andreelli, F.; Viollet, B. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest., 2010, 120(7), 2355-2369.
[http://dx.doi.org/10.1172/JCI40671] [PMID: 20577053]
[87]
Momcilovic, M.; Shackelford, D.B. Targeting LKB1 in cancer - exposing and exploiting vulnerabilities. Br. J. Cancer, 2015, 113(4), 574-584.
[http://dx.doi.org/10.1038/bjc.2015.261] [PMID: 26196184]
[88]
Hawley, S.A.; Boudeau, J.; Reid, J.L.; Mustard, K.J.; Udd, L.; Mäkelä, T.P.; Alessi, D.R.; Hardie, D.G. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J. Biol., 2003, 2(4), 28.
[http://dx.doi.org/10.1186/1475-4924-2-28] [PMID: 14511394]
[89]
Woods, A.; Johnstone, S.R.; Dickerson, K.; Leiper, F.C.; Fryer, L.G.; Neumann, D.; Schlattner, U.; Wallimann, T.; Carlson, M.; Carling, D. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol., 2003, 13(22), 2004-2008.
[http://dx.doi.org/10.1016/j.cub.2003.10.031] [PMID: 14614828]
[90]
Shaw, R.J.; Kosmatka, M.; Bardeesy, N.; Hurley, R.L.; Witters, L.A.; DePinho, R.A.; Cantley, L.C. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl. Acad. Sci. USA, 2004, 101(10), 3329-3335.
[http://dx.doi.org/10.1073/pnas.0308061100] [PMID: 14985505]
[91]
Inoki, K.; Zhu, T.; Guan, K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell, 2003, 115(5), 577-590.
[http://dx.doi.org/10.1016/S0092-8674(03)00929-2] [PMID: 14651849]
[92]
Jones, R.G.; Plas, D.R.; Kubek, S.; Buzzai, M.; Mu, J.; Xu, Y.; Birnbaum, M.J.; Thompson, C.B. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell, 2005, 18(3), 283-293.
[http://dx.doi.org/10.1016/j.molcel.2005.03.027] [PMID: 15866171]
[93]
Faubert, B.; Boily, G.; Izreig, S.; Griss, T.; Samborska, B.; Dong, Z.; Dupuy, F.; Chambers, C.; Fuerth, B.J.; Viollet, B.; Mamer, O.A.; Avizonis, D.; DeBerardinis, R.J.; Siegel, P.M.; Jones, R.G. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab., 2013, 17(1), 113-124.
[http://dx.doi.org/10.1016/j.cmet.2012.12.001] [PMID: 23274086]
[94]
Huang, X.; Wullschleger, S.; Shpiro, N.; McGuire, V.A.; Sakamoto, K.; Woods, Y.L.; McBurnie, W.; Fleming, S.; Alessi, D.R. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem. J., 2008, 412(2), 211-221.
[http://dx.doi.org/10.1042/BJ20080557] [PMID: 18387000]
[95]
Shackelford, D.B.; Abt, E.; Gerken, L.; Vasquez, D.S.; Seki, A.; Leblanc, M.; Wei, L.; Fishbein, M.C.; Czernin, J.; Mischel, P.S.; Shaw, R.J. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell, 2013, 23(2), 143-158.
[http://dx.doi.org/10.1016/j.ccr.2012.12.008] [PMID: 23352126]
[96]
Saito, Y.; Chapple, R.H.; Lin, A.; Kitano, A.; Nakada, D. AMPK Protects Leukemia-Initiating Cells in Myeloid Leukemias from Metabolic Stress in the Bone Marrow. Cell Stem Cell, 2015, 17(5), 585-596.
[http://dx.doi.org/10.1016/j.stem.2015.08.019] [PMID: 26440282]
[97]
Kishton, R.J.; Barnes, C.E.; Nichols, A.G.; Cohen, S.; Gerriets, V.A.; Siska, P.J.; Macintyre, A.N.; Goraksha-Hicks, P.; de Cubas, A.A.; Liu, T.; Warmoes, M.O.; Abel, E.D.; Yeoh, A.E.; Gershon, T.R.; Rathmell, W.K.; Richards, K.L.; Locasale, J.W.; Rathmell, J.C. AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival. Cell Metab., 2016, 23(4), 649-662.
[http://dx.doi.org/10.1016/j.cmet.2016.03.008] [PMID: 27076078]
[98]
Green, A.S.; Chapuis, N.; Maciel, T.T.; Willems, L.; Lambert, M.; Arnoult, C.; Boyer, O.; Bardet, V.; Park, S.; Foretz, M.; Viollet, B.; Ifrah, N.; Dreyfus, F.; Hermine, O.; Moura, I.C.; Lacombe, C.; Mayeux, P.; Bouscary, D.; Tamburini, J. The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation. Blood, 2010, 116(20), 4262-4273.
[http://dx.doi.org/10.1182/blood-2010-02-269837] [PMID: 20668229]
[99]
Jude, J.G.; Spencer, G.J.; Huang, X.; Somerville, T.D.D.; Jones, D.R.; Divecha, N.; Somervaille, T.C.P. A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival. Oncogene, 2015, 34(10), 1253-1262.
[http://dx.doi.org/10.1038/onc.2014.77] [PMID: 24681948]
[100]
Visconte, V.; Przychodzen, B.; Han, Y.; Nawrocki, S.T.; Thota, S.; Kelly, K.R.; Patel, B.J.; Hirsch, C.; Advani, A.S.; Carraway, H.E.; Sekeres, M.A.; Maciejewski, J.P.; Carew, J.S. Complete mutational spectrum of the autophagy interactome: a novel class of tumor suppressor genes in myeloid neoplasms. Leukemia, 2017, 31(2), 505-510.
[http://dx.doi.org/10.1038/leu.2016.295] [PMID: 27773925]
[101]
Monteverde, T.; Muthalagu, N.; Port, J.; Murphy, D.J. Evidence of cancer-promoting roles for AMPK and related kinases. FEBS J., 2015, 282(24), 4658-4671.
[http://dx.doi.org/10.1111/febs.13534] [PMID: 26426570]
[102]
Sujobert, P.; Poulain, L.; Paubelle, E.; Zylbersztejn, F.; Grenier, A.; Lambert, M.; Townsend, E.C.; Brusq, J.M.; Nicodeme, E.; Decrooqc, J.; Nepstad, I.; Green, A.S.; Mondesir, J.; Hospital, M.A.; Jacque, N.; Christodoulou, A.; Desouza, T.A.; Hermine, O.; Foretz, M.; Viollet, B.; Lacombe, C.; Mayeux, P.; Weinstock, D.M.; Moura, I.C.; Bouscary, D.; Tamburini, J. Co-activation of AMPK and mTORC1 induces cytotoxicity in acute myeloid leukemia. Cell Reports, 2015, 11(9), 1446-1457.
[http://dx.doi.org/10.1016/j.celrep.2015.04.063] [PMID: 26004183]
[103]
Yasinska, I.M.; Gibbs, B.F.; Lall, G.S.; Sumbayev, V.V. The HIF-1 transcription complex is essential for translational control of myeloid hematopoietic cell function by maintaining mTOR phosphorylation. Cell. Mol. Life Sci., 2014, 71(4), 699-710.
[http://dx.doi.org/10.1007/s00018-013-1421-2] [PMID: 23872956]
[104]
Tabe, Y.; Yamamoto, S.; Saitoh, K.; Sekihara, K.; Monma, N.; Ikeo, K.; Mogushi, K.; Shikami, M.; Ruvolo, V.; Ishizawa, J.; Hail, N., Jr; Kazuno, S.; Igarashi, M.; Matsushita, H.; Yamanaka, Y.; Arai, H.; Nagaoka, I.; Miida, T.; Hayashizaki, Y.; Konopleva, M.; Andreeff, M. Bone marrow adipocytes facilitate fatty acid oxidation activating AMPK and a transcriptional network supporting survival of acute monocytic leukemia cells. Cancer Res., 2017, 77(6), 1453-1464.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-1645] [PMID: 28108519]
[105]
Pryor, R.; Cabreiro, F. Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem. J., 2015, 471(3), 307-322.
[http://dx.doi.org/10.1042/BJ20150497] [PMID: 26475449]
[106]
Christodoulou, M.I.; Scorilas, A. Metformin and Anti-Cancer Therapeutics: Hopes for a More Enhanced Armamentarium Against Human Neoplasias? Curr. Med. Chem., 2017, 24(1), 14-56.
[http://dx.doi.org/10.2174/0929867323666160907161459] [PMID: 27604091]
[107]
Chae, Y.K.; Arya, A.; Malecek, M.K.; Shin, D.S.; Carneiro, B.; Chandra, S.; Kaplan, J.; Kalyan, A.; Altman, J.K.; Platanias, L.; Giles, F. Repurposing metformin for cancer treatment: current clinical studies. Oncotarget, 2016, 7(26), 40767-40780.
[http://dx.doi.org/10.18632/oncotarget.8194] [PMID: 27004404]
[108]
Rosilio, C.; Ben-Sahra, I.; Bost, F.; Peyron, J.F. Metformin: a metabolic disruptor and anti-diabetic drug to target human leukemia. Cancer Lett., 2014, 346(2), 188-196.
[http://dx.doi.org/10.1016/j.canlet.2014.01.006] [PMID: 24462823]
[109]
Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; Musi, N.; Hirshman, M.F.; Goodyear, L.J.; Moller, D.E. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest., 2001, 108(8), 1167-1174.
[http://dx.doi.org/10.1172/JCI13505] [PMID: 11602624]
[110]
Turban, S.; Stretton, C.; Drouin, O.; Green, C.J.; Watson, M.L.; Gray, A.; Ross, F.; Lantier, L.; Viollet, B.; Hardie, D.G.; Marette, A.; Hundal, H.S. Defining the contribution of AMP-activated protein kinase (AMPK) and protein kinase C (PKC) in regulation of glucose uptake by metformin in skeletal muscle cells. J. Biol. Chem., 2012, 287(24), 20088-20099.
[http://dx.doi.org/10.1074/jbc.M111.330746] [PMID: 22511782]
[111]
Evans, J.M.; Donnelly, L.A.; Emslie-Smith, A.M.; Alessi, D.R.; Morris, A.D. Metformin and reduced risk of cancer in diabetic patients. BMJ, 2005, 330(7503), 1304-1305.
[http://dx.doi.org/10.1136/bmj.38415.708634.F7] [PMID: 15849206]
[112]
Lee, D.K.; Szabo, E. Repurposing Drugs for Cancer Prevention. Curr. Top. Med. Chem., 2016, 16(19), 2169-2178.
[http://dx.doi.org/10.2174/1568026616666160216154946] [PMID: 26881711]
[113]
Kordes, S.; Pollak, M.N.; Zwinderman, A.H.; Mathôt, R.A.; Weterman, M.J.; Beeker, A.; Punt, C.J.; Richel, D.J.; Wilmink, J.W. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol., 2015, 16(7), 839-847.
[http://dx.doi.org/10.1016/S1470-2045(15)00027-3] [PMID: 26067687]
[114]
Reni, M.; Dugnani, E.; Cereda, S.; Belli, C.; Balzano, G.; Nicoletti, R.; Liberati, D.; Pasquale, V.; Scavini, M.; Maggiora, P.; Sordi, V.; Lampasona, V.; Ceraulo, D.; Di Terlizzi, G.; Doglioni, C.; Falconi, M.; Piemonti, L. (Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial. Clin. Cancer Res., 2016, 22(5), 1076-1085.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1722] [PMID: 26459175]
[115]
ClinicalTrials.gov. a service of the U.S. National Institutes of Health. clinicaltrials.gov.,
[116]
Zakikhani, M.; Dowling, R.; Fantus, I.G.; Sonenberg, N.; Pollak, M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res., 2006, 66(21), 10269-10273.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-1500] [PMID: 17062558]
[117]
El-Mir, M.Y.; Nogueira, V.; Fontaine, E.; Avéret, N.; Rigoulet, M.; Leverve, X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem., 2000, 275(1), 223-228.
[http://dx.doi.org/10.1074/jbc.275.1.223] [PMID: 10617608]
[118]
Hawley, S.A.; Gadalla, A.E.; Olsen, G.S.; Hardie, D.G. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes, 2002, 51(8), 2420-2425.
[http://dx.doi.org/10.2337/diabetes.51.8.2420] [PMID: 12145153]
[119]
Zou, M.H.; Hou, X.Y.; Shi, C.M.; Kirkpatick, S.; Liu, F.; Goldman, M.H.; Cohen, R.A. Activation of 5′-AMP-activated kinase is mediated through c-Src and phosphoinositide 3-kinase activity during hypoxia-reoxygenation of bovine aortic endothelial cells. Role of peroxynitrite. J. Biol. Chem., 2003, 278(36), 34003-34010.
[http://dx.doi.org/10.1074/jbc.M300215200] [PMID: 12824177]
[120]
Xie, Z.; Dong, Y.; Scholz, R.; Neumann, D.; Zou, M.H. Phosphorylation of LKB1 at serine 428 by protein kinase C-zeta is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation, 2008, 117(7), 952-962.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.744490] [PMID: 18250273]
[121]
Ben Sahra, I.; Regazzetti, C.; Robert, G.; Laurent, K.; Le Marchand-Brustel, Y.; Auberger, P.; Tanti, J.F.; Giorgetti-Peraldi, S.; Bost, F. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res., 2011, 71(13), 4366-4372.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-1769] [PMID: 21540236]
[122]
Yi, Y.; Chen, D.; Ao, J.; Sun, S.; Wu, M.; Li, X.; Bergholz, J.; Zhang, Y.; Xiao, Z.X. Metformin Promotes AMP-activated Protein Kinase-independent Suppression of ΔNp63α Protein Expression and Inhibits Cancer Cell Viability. J. Biol. Chem., 2017, 292(13), 5253-5261.
[http://dx.doi.org/10.1074/jbc.M116.769141] [PMID: 28193839]
[123]
Foretz, M.; Guigas, B.; Bertrand, L.; Pollak, M.; Viollet, B. Metformin: from mechanisms of action to therapies. Cell Metab., 2014, 20(6), 953-966.
[http://dx.doi.org/10.1016/j.cmet.2014.09.018] [PMID: 25456737]
[124]
Wu, L.; Zhu, J.; Prokop, L.J.; Murad, M.H. Pharmacologic Therapy of Diabetes and Overall Cancer Risk and Mortality: A Meta-Analysis of 265 Studies. Sci. Rep., 2015, 5, 10147.
[http://dx.doi.org/10.1038/srep10147] [PMID: 26076034]
[125]
Vakana, E.; Altman, J.K.; Glaser, H.; Donato, N.J.; Platanias, L.C. Antileukemic effects of AMPK activators on BCR-ABL-expressing cells. Blood, 2011, 118(24), 6399-6402.
[http://dx.doi.org/10.1182/blood-2011-01-332783] [PMID: 22021366]
[126]
Rosilio, C.; Lounnas, N.; Nebout, M.; Imbert, V.; Hagenbeek, T.; Spits, H.; Asnafi, V.; Pontier-Bres, R.; Reverso, J.; Michiels, J.F.; Sahra, I.B.; Bost, F.; Peyron, J.F. The metabolic perturbators metformin, phenformin and AICAR interfere with the growth and survival of murine PTEN-deficient T cell lymphomas and human T-ALL/T-LL cancer cells. Cancer Lett., 2013, 336(1), 114-126.
[http://dx.doi.org/10.1016/j.canlet.2013.04.015] [PMID: 23612073]
[127]
Jagannathan, S.; Abdel-Malek, M.A.; Malek, E.; Vad, N.; Latif, T.; Anderson, K.C.; Driscoll, J.J. Pharmacologic screens reveal metformin that suppresses GRP78-dependent autophagy to enhance the anti-myeloma effect of bortezomib. Leukemia, 2015, 29(11), 2184-2191.
[http://dx.doi.org/10.1038/leu.2015.157] [PMID: 26108695]
[128]
Shi, W.Y.; Xiao, D.; Wang, L.; Dong, L.H.; Yan, Z.X.; Shen, Z.X.; Chen, S.J.; Chen, Y.; Zhao, W.L. Therapeutic metformin/ AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis, 2012. 3e275
[129]
Leclerc, G.M.; Leclerc, G.J.; Kuznetsov, J.N.; DeSalvo, J.; Barredo, J.C. Metformin induces apoptosis through AMPK-dependent inhibition of UPR signaling in ALL lymphoblasts. PLoS One, 2013, 8(8), e74420.
[http://dx.doi.org/10.1371/journal.pone.0074420] [PMID: 24009772]
[130]
Yi, Y.; Gao, L.; Wu, M.; Ao, J.; Zhang, C.; Wang, X.; Lin, M.; Bergholz, J.; Zhang, Y.; Xiao, Z.J. Metformin sensitizes leukemia cells to vincristine via activation of AMP-activated protein kinase. J. Cancer, 2017, 8(13), 2636-2642.
[http://dx.doi.org/10.7150/jca.19873] [PMID: 28900501]
[131]
Scotland, S.; Saland, E.; Skuli, N.; de Toni, F.; Boutzen, H.; Micklow, E.; Sénégas, I.; Peyraud, R.; Peyriga, L.; Théodoro, F.; Dumon, E.; Martineau, Y.; Danet-Desnoyers, G.; Bono, F.; Rocher, C.; Levade, T.; Manenti, S.; Junot, C.; Portais, J.C.; Alet, N.; Récher, C.; Selak, M.A.; Carroll, M.; Sarry, J.E. Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells. Leukemia, 2013, 27(11), 2129-2138.
[http://dx.doi.org/10.1038/leu.2013.107] [PMID: 23568147]
[132]
Ceacareanu, A.C.; Nimako, G.K.; Wintrob, Z.A.P. Missing the benefit of metformin in acute myeloid leukemia: A problem of contrast? J. Res. Pharm. Pract., 2017, 6(3), 145-150.
[http://dx.doi.org/10.4103/jrpp.JRPP_17_37] [PMID: 29026839]
[133]
Huai, L.; Wang, C.; Zhang, C.; Li, Q.; Chen, Y.; Jia, Y.; Li, Y.; Xing, H.; Tian, Z.; Rao, Q.; Wang, M.; Wang, J. Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway. Biochem. Biophys. Res. Commun., 2012, 422(3), 398-404.
[http://dx.doi.org/10.1016/j.bbrc.2012.05.001] [PMID: 22575507]
[134]
Kawashima, I.; Mitsumori, T.; Nozaki, Y.; Yamamoto, T.; Shobu-Sueki, Y.; Nakajima, K.; Kirito, K. Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cells. Exp. Hematol., 2015, 43(7), 524-33.e1.
[http://dx.doi.org/10.1016/j.exphem.2015.03.005] [PMID: 25846811]
[135]
Miranda, M.B.; McGuire, T.F.; Johnson, D.E. Importance of MEK-1/-2 signaling in monocytic and granulocytic differentiation of myeloid cell lines. Leukemia, 2002, 16(4), 683-692.
[http://dx.doi.org/10.1038/sj.leu.2402400] [PMID: 11960350]
[136]
Vasamsetti, S.B.; Karnewar, S.; Kanugula, A.K.; Thatipalli, A.R.; Kumar, J.M.; Kotamraju, S. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes, 2015, 64(6), 2028-2041.
[http://dx.doi.org/10.2337/db14-1225] [PMID: 25552600]
[137]
Eikawa, S.; Nishida, M.; Mizukami, S.; Yamazaki, C.; Nakayama, E.; Udono, H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc. Natl. Acad. Sci. USA, 2015, 112(6), 1809-1814.
[http://dx.doi.org/10.1073/pnas.1417636112] [PMID: 25624476]
[138]
Limagne, E.; Thibaudin, M.; Euvrard, R.; Berger, H.; Chalons, P.; Végan, F.; Humblin, E.; Boidot, R.; Rébé, C.; Derangère, V.; Ladoire, S.; Apetoh, L.; Delmas, D.; Ghiringhelli, F. Sirtuin-1 Activation Controls Tumor Growth by Impeding Th17 Differentiation via STAT3 Deacetylation. Cell Reports, 2017, 19(4), 746-759.
[http://dx.doi.org/10.1016/j.celrep.2017.04.004] [PMID: 28445726]
[139]
Liu, X.; Zheng, H.; Yu, W.M.; Cooper, T.M.; Bunting, K.D.; Qu, C.K. Maintenance of mouse hematopoietic stem cells ex vivo by reprogramming cellular metabolism. Blood, 2015, 125(10), 1562-1565.
[http://dx.doi.org/10.1182/blood-2014-04-568949] [PMID: 25593337]
[140]
Zhang, Q.S.; Tang, W.; Deater, M.; Phan, N.; Marcogliese, A.N.; Li, H.; Al-Dhalimy, M.; Major, A.; Olson, S.; Monnat, R.J., Jr; Grompe, M. Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice. Blood, 2016, 128(24), 2774-2784.
[http://dx.doi.org/10.1182/blood-2015-11-683490] [PMID: 27756748]
[141]
Van Den Neste, E.; Van den Berghe, G.; Bontemps, F. AICA-riboside (acadesine), an activator of AMP-activated protein kinase with potential for application in hematologic malignancies. Expert Opin. Investig. Drugs, 2010, 19(4), 571-578.
[http://dx.doi.org/10.1517/13543781003703694] [PMID: 20367195]
[142]
Pinson, B.; Vaur, S.; Sagot, I.; Coulpier, F.; Lemoine, S.; Daignan-Fornier, B. Metabolic intermediates selectively stimulate transcription factor interaction and modulate phosphate and purine pathways. Genes Dev., 2009, 23(12), 1399-1407.
[http://dx.doi.org/10.1101/gad.521809] [PMID: 19528318]
[143]
Daignan-Fornier, B.; Pinson, B. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5′-monophosphate (AICAR), a highly conserved purine intermediate with multiple effects. Metabolites, 2012, 2(2), 292-302.
[http://dx.doi.org/10.3390/metabo2020292] [PMID: 24957512]
[144]
Mangano, D.T. Effects of acadesine on myocardial infarction, stroke, and death following surgery. A meta-analysis of the 5 international randomized trials. The Multicenter Study of Perioperative Ischemia (McSPI) Research Group. JAMA, 1997, 277(4), 325-332.
[http://dx.doi.org/10.1001/jama.1997.03540280063035] [PMID: 9002496]
[145]
Henin, N.; Vincent, M.F.; Gruber, H.E.; Van den Berghe, G. Inhibition of fatty acid and cholesterol synthesis by stimulation of AMP-activated protein kinase. FASEB J., 1995, 9(7), 541-546.
[http://dx.doi.org/10.1096/fasebj.9.7.7737463] [PMID: 7737463]
[146]
Corton, J.M.; Gillespie, J.G.; Hawley, S.A.; Hardie, D.G. 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.
[http://dx.doi.org/10.1111/j.1432-1033.1995.tb20498.x] [PMID: 7744080]
[147]
Narkar, V.A.; Downes, M.; Yu, R.T.; Embler, E.; Wang, Y.X.; Banayo, E.; Mihaylova, M.M.; Nelson, M.C.; Zou, Y.; Juguilon, H.; Kang, H.; Shaw, R.J.; Evans, R.M. AMPK and PPARdelta agonists are exercise mimetics. Cell, 2008, 134(3), 405-415.
[http://dx.doi.org/10.1016/j.cell.2008.06.051] [PMID: 18674809]
[148]
Lanner, J.T.; Georgiou, D.K.; Dagnino-Acosta, A.; Ainbinder, A.; Cheng, Q.; Joshi, A.D.; Chen, Z.; Yarotskyy, V.; Oakes, J.M.; Lee, C.S.; Monroe, T.O.; Santillan, A.; Dong, K.; Goodyear, L.; Ismailov, I.I.; Rodney, G.G.; Dirksen, R.T.; Hamilton, S.L. AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation. Nat. Med., 2012, 18(2), 244-251.
[http://dx.doi.org/10.1038/nm.2598] [PMID: 22231556]
[149]
Bost, F.; Decoux-Poullot, A.G.; Tanti, J.F.; Clavel, S. Energy disruptors: rising stars in anticancer therapy? Oncogenesis, 2016. 5e188
[150]
Merrill, G.F.; Kurth, E.J.; Hardie, D.G.; Winder, W.W. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am. J. Physiol., 1997, 273(6 Pt 1), E1107-E1112.
[PMID: 9435525]
[151]
Vincent, M.F.; Erion, M.D.; Gruber, H.E.; Van den Berghe, G. Hypoglycaemic effect of AICAriboside in mice. Diabetologia, 1996, 39(10), 1148-1155.
[http://dx.doi.org/10.1007/BF02658500] [PMID: 8897001]
[152]
Bergeron, R.; Previs, S.F.; Cline, G.W.; Perret, P.; Russell, R.R., III; Young, L.H.; Shulman, G.I. Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes, 2001, 50(5), 1076-1082.
[http://dx.doi.org/10.2337/diabetes.50.5.1076] [PMID: 11334411]
[153]
Cuthbertson, D.J.; Babraj, J.A.; Mustard, K.J.; Towler, M.C.; Green, K.A.; Wackerhage, H.; Leese, G.P.; Baar, K.; Thomason-Hughes, M.; Sutherland, C.; Hardie, D.G.; Rennie, M.J. 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men. Diabetes, 2007, 56(8), 2078-2084.
[http://dx.doi.org/10.2337/db06-1716] [PMID: 17513706]
[154]
McGee, S.L.; van Denderen, B.J.; Howlett, K.F.; Mollica, J.; Schertzer, J.D.; Kemp, B.E.; Hargreaves, M. AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes, 2008, 57(4), 860-867.
[http://dx.doi.org/10.2337/db07-0843] [PMID: 18184930]
[155]
Mu, J.; Brozinick, J.T., Jr; Valladares, O.; Bucan, M.; Birnbaum, M.J. A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol. Cell, 2001, 7(5), 1085-1094.
[http://dx.doi.org/10.1016/S1097-2765(01)00251-9] [PMID: 11389854]
[156]
Dzamko, N.; Schertzer, J.D.; Ryall, J.G.; Steel, R.; Macaulay, S.L.; Wee, S.; Chen, Z.P.; Michell, B.J.; Oakhill, J.S.; Watt, M.J.; Jørgensen, S.B.; Lynch, G.S.; Kemp, B.E.; Steinberg, G.R. AMPK-independent pathways regulate skeletal muscle fatty acid oxidation. J. Physiol., 2008, 586(23), 5819-5831.
[http://dx.doi.org/10.1113/jphysiol.2008.159814] [PMID: 18845612]
[157]
Dixon, R.; Gourzis, J.; McDermott, D.; Fujitaki, J.; Dewland, P.; Gruber, H. AICA-riboside: safety, tolerance, and pharmacokinetics of a novel adenosine-regulating agent. J. Clin. Pharmacol., 1991, 31(4), 342-347.
[http://dx.doi.org/10.1002/j.1552-4604.1991.tb03715.x] [PMID: 2037706]
[158]
Drew, B.G.; Kingwell, B.A. Acadesine, an adenosine-regulating agent with the potential for widespread indications. Expert Opin. Pharmacother., 2008, 9(12), 2137-2144.
[http://dx.doi.org/10.1517/14656566.9.12.2137] [PMID: 18671468]
[159]
Mangano, D.T.; Miao, Y.; Tudor, I.C.; Dietzel, C. Post-reperfusion myocardial infarction: long-term survival improvement using adenosine regulation with acadesine. J. Am. Coll. Cardiol., 2006, 48(1), 206-214.
[http://dx.doi.org/10.1016/j.jacc.2006.04.044] [PMID: 16814669]
[160]
Newman, M.F.; Ferguson, T.B.; White, J.A.; Ambrosio, G.; Koglin, J.; Nussmeier, N.A.; Pearl, R.G.; Pitt, B.; Wechsler, A.S.; Weisel, R.D.; Reece, T.L.; Lira, A.; Harrington, R.A. Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial. JAMA, 2012, 308(2), 157-164.
[http://dx.doi.org/10.1001/jama.2012.7633] [PMID: 22782417]
[161]
Szentmiklósi, A.J.; Cseppento, A.; Harmati, G.; Nánási, P.P. Novel trends in the treatment of cardiovascular disorders: site- and event- selective adenosinergic drugs. Curr. Med. Chem., 2011, 18(8), 1164-1187.
[http://dx.doi.org/10.2174/092986711795029753] [PMID: 21291368]
[162]
Fischetto, G.; Bermon, S. From gene engineering to gene modulation and manipulation: can we prevent or detect gene doping in sports? Sports Med., 2013, 43(10), 965-977.
[http://dx.doi.org/10.1007/s40279-013-0075-4] [PMID: 23832852]
[163]
Pokrywka, A.; Cholbinski, P.; Kaliszewski, P.; Kowalczyk, K.; Konczak, D.; Zembron-Lacny, A. Metabolic modulators of the exercise response: doping control analysis of an agonist of the peroxisome proliferator-activated receptor δ (GW501516) and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). J. Physiol. Pharmacol., 2014, 65(4), 469-476.
[PMID: 25179079]
[164]
Campàs, C.; Lopez, J.M.; Santidrián, A.F.; Barragán, M.; Bellosillo, B.; Colomer, D.; Gil, J. Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes. Blood, 2003, 101(9), 3674-3680.
[http://dx.doi.org/10.1182/blood-2002-07-2339] [PMID: 12522004]
[165]
Van Den Neste, E.; Cazin, B.; Janssens, A.; González-Barca, E.; Terol, M.J.; Levy, V.; Pérez de Oteyza, J.; Zachee, P.; Saunders, A.; de Frias, M.; Campàs, C. Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study. Cancer Chemother. Pharmacol., 2013, 71(3), 581-591.
[http://dx.doi.org/10.1007/s00280-012-2033-5] [PMID: 23228986]
[166]
Campàs, C.; Santidrián, A.F.; Domingo, A.; Gil, J. Acadesine induces apoptosis in B cells from mantle cell lymphoma and splenic marginal zone lymphoma. Leukemia, 2005, 19(2), 292-294.
[http://dx.doi.org/10.1038/sj.leu.2403593] [PMID: 15549145]
[167]
Sengupta, T.K.; Leclerc, G.M.; Hsieh-Kinser, T.T.; Leclerc, G.J.; Singh, I.; Barredo, J.C. Cytotoxic effect of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) on childhood acute lymphoblastic leukemia (ALL) cells: implication for targeted therapy. Mol. Cancer, 2007, 6, 46.
[http://dx.doi.org/10.1186/1476-4598-6-46] [PMID: 17623090]
[168]
Robert, G.; Ben Sahra, I.; Puissant, A.; Colosetti, P.; Belhacene, N.; Gounon, P.; Hofman, P.; Bost, F.; Cassuto, J.P.; Auberger, P. Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death. PLoS One, 2009, 4(11), e7889.
[http://dx.doi.org/10.1371/journal.pone.0007889] [PMID: 19924252]
[169]
Santidrián, A.F.; González-Gironès, D.M.; Iglesias-Serret, D.; Coll-Mulet, L.; Cosialls, A.M.; de Frias, M.; Campàs, C.; González-Barca, E.; Alonso, E.; Labi, V.; Viollet, B.; Benito, A.; Pons, G.; Villunger, A.; Gil, J. AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells. Blood, 2010, 116(16), 3023-3032.
[http://dx.doi.org/10.1182/blood-2010-05-283960] [PMID: 20664053]
[170]
Montraveta, A.; Xargay-Torrent, S.; López-Guerra, M.; Rosich, L.; Pérez-Galán, P.; Salaverria, I.; Beà, S.; Kalko, S.G.; de Frias, M.; Campàs, C.; Roué, G.; Colomer, D. Synergistic anti-tumor activity of acadesine (AICAR) in combination with the anti-CD20 monoclonal antibody rituximab in in vivo and in vitro models of mantle cell lymphoma. Oncotarget, 2014, 5(3), 726-739.
[http://dx.doi.org/10.18632/oncotarget.1455] [PMID: 24519895]
[171]
Montraveta, A.; Xargay-Torrent, S.; Rosich, L.; López-Guerra, M.; Roldán, J.; Rodríguez, V.; Lee-Vergés, E.; de Frías, M.; Campàs, C.; Campo, E.; Roué, G.; Colomer, D. Bcl-2high mantle cell lymphoma cells are sensitized to acadesine with ABT-199. Oncotarget, 2015, 6(25), 21159-21172.
[http://dx.doi.org/10.18632/oncotarget.4230] [PMID: 26110568]
[172]
Zang, Y.; Yu, L.F.; Pang, T.; Fang, L.P.; Feng, X.; Wen, T.Q.; Nan, F.J.; Feng, L.Y.; Li, J. AICAR induces astroglial differentiation of neural stem cells via activating the JAK/STAT3 pathway independently of AMP-activated protein kinase. J. Biol. Chem., 2008, 283(10), 6201-6208.
[http://dx.doi.org/10.1074/jbc.M708619200] [PMID: 18077446]
[173]
Sun, X.; Yang, Q.; Rogers, C.J.; Du, M.; Zhu, M.J. AMPK improves gut epithelial differentiation and barrier function via regulating Cdx2 expression. Cell Death Differ., 2017, 24(5), 819-831.
[http://dx.doi.org/10.1038/cdd.2017.14] [PMID: 28234358]
[174]
Chae, H.D.; Lee, M.R.; Broxmeyer, H.E. 5-Aminoimidazole-4-carboxyamide ribonucleoside induces G(1)/S arrest and Nanog downregulation via p53 and enhances erythroid differentiation. Stem Cells, 2012, 30(2), 140-149.
[http://dx.doi.org/10.1002/stem.778] [PMID: 22076938]
[175]
Johnson, D.E.; Redner, R.L. An ATRActive future for differentiation therapy in AML. Blood Rev., 2015, 29(4), 263-268.
[http://dx.doi.org/10.1016/j.blre.2015.01.002] [PMID: 25631637]
[176]
H. Differentiation therapy revisited. Nat. Rev. Cancer, 2017.
[http://dx.doi.org/10.1038/nrc.2017.103]
[177]
Xie, N.; Zhong, L.; Liu, L.; Fang, Y.; Qi, X.; Cao, J.; Yang, B.; He, Q.; Ying, M. Autophagy contributes to dasatinib-induced myeloid differentiation of human acute myeloid leukemia cells. Biochem. Pharmacol., 2014, 89(1), 74-85.
[http://dx.doi.org/10.1016/j.bcp.2014.02.019] [PMID: 24607273]
[178]
Dembitz, V.; Lalic, H.; Visnjic, D. 5-Aminoimidazole-4-carboxamide ribonucleoside-induced autophagy flux during differentiation of monocytic leukemia cells. Cell Death Discov., 2017, 3, 17066.
[http://dx.doi.org/10.1038/cddiscovery.2017.66] [PMID: 28975042]
[179]
Velez, J.; Pan, R.; Lee, J.T.; Enciso, L.; Suarez, M.; Duque, J.E.; Jaramillo, D.; Lopez, C.; Morales, L.; Bornmann, W.; Konopleva, M.; Krystal, G.; Andreeff, M.; Samudio, I. Biguanides sensitize leukemia cells to ABT-737-induced apoptosis by inhibiting mitochondrial electron transport. Oncotarget, 2016, 7(32), 51435-51449.
[http://dx.doi.org/10.18632/oncotarget.9843] [PMID: 27283492]
[180]
Visnjic, D.; Lalic, H.; Dembitz, V.; Banfic, H. Metabolism and differentiation. Period. Biol., 2014, 116, 37-43.
[181]
Samudio, I.; Harmancey, R.; Fiegl, M.; Kantarjian, H.; Konopleva, M.; Korchin, B.; Kaluarachchi, K.; Bornmann, W.; Duvvuri, S.; Taegtmeyer, H.; Andreeff, M. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J. Clin. Invest., 2010, 120(1), 142-156.
[http://dx.doi.org/10.1172/JCI38942] [PMID: 20038799]
[182]
Skrtić, M.; Sriskanthadevan, S.; Jhas, B.; Gebbia, M.; Wang, X.; Wang, Z.; Hurren, R.; Jitkova, Y.; Gronda, M.; Maclean, N.; Lai, C.K.; Eberhard, Y.; Bartoszko, J.; Spagnuolo, P.; Rutledge, A.C.; Datti, A.; Ketela, T.; Moffat, J.; Robinson, B.H.; Cameron, J.H.; Wrana, J.; Eaves, C.J.; Minden, M.D.; Wang, J.C.; Dick, J.E.; Humphries, K.; Nislow, C.; Giaever, G.; Schimmer, A.D. Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell, 2011, 20(5), 674-688.
[http://dx.doi.org/10.1016/j.ccr.2011.10.015] [PMID: 22094260]
[183]
Poulain, L.; Sujobert, P.; Zylbersztejn, F.; Barreau, S.; Stuani, L.; Lambert, M.; Palama, T.L.; Chesnais, V.; Birsen, R.; Vergez, F.; Farge, T.; Chenevier-Gobeaux, C.; Fraisse, M.; Bouillaud, F.; Debeissat, C.; Herault, O.; Récher, C.; Lacombe, C.; Fontenay, M.; Mayeux, P.; Maciel, T.T.; Portais, J.C.; Sarry, J.E.; Tamburini, J.; Bouscary, D.; Chapuis, N. High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells. Leukemia, 2017, 31(11), 2326-2335.
[http://dx.doi.org/10.1038/leu.2017.81] [PMID: 28280275]
[184]
Jacque, N.; Ronchetti, A.M.; Larrue, C.; Meunier, G.; Birsen, R.; Willems, L.; Saland, E.; Decroocq, J.; Maciel, T.T.; Lambert, M.; Poulain, L.; Hospital, M.A.; Sujobert, P.; Joseph, L.; Chapuis, N.; Lacombe, C.; Moura, I.C.; Demo, S.; Sarry, J.E.; Recher, C.; Mayeux, P.; Tamburini, J.; Bouscary, D. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood, 2015, 126(11), 1346-1356.
[http://dx.doi.org/10.1182/blood-2015-01-621870] [PMID: 26186940]
[185]
Sykes, D.B.; Kfoury, Y.S.; Mercier, F.E.; Wawer, M.J.; Law, J.M.; Haynes, M.K.; Lewis, T.A.; Schajnovitz, A.; Jain, E.; Lee, D.; Meyer, H.; Pierce, K.A.; Tolliday, N.J.; Waller, A.; Ferrara, S.J.; Eheim, A.L.; Stoeckigt, D.; Maxcy, K.L.; Cobert, J.M.; Bachand, J.; Szekely, B.A.; Mukherjee, S.; Sklar, L.A.; Kotz, J.D.; Clish, C.B.; Sadreyev, R.I.; Clemons, P.A.; Janzer, A.; Schreiber, S.L.; Scadden, D.T. Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia. Cell, 2016, 167(1), 171-186.e15.
[http://dx.doi.org/10.1016/j.cell.2016.08.057] [PMID: 27641501]
[186]
Pikman, Y.; Puissant, A.; Alexe, G.; Furman, A.; Chen, L.M.; Frumm, S.M.; Ross, L.; Fenouille, N.; Bassil, C.F.; Lewis, C.A.; Ramos, A.; Gould, J.; Stone, R.M.; DeAngelo, D.J.; Galinsky, I.; Clish, C.B.; Kung, A.L.; Hemann, M.T.; Vander Heiden, M.G.; Banerji, V.; Stegmaier, K. Targeting MTHFD2 in acute myeloid leukemia. J. Exp. Med., 2016, 213(7), 1285-1306.
[http://dx.doi.org/10.1084/jem.20151574] [PMID: 27325891]
[187]
Amatangelo, M.D.; Quek, L.; Shih, A.; Stein, E.M.; Roshal, M.; David, M.D.; Marteyn, B.; Rahnamay Farnoud, N.; de Botton, S.; Bernard, O.A.; Wu, B.; Yen, K.E.; Tallman, M.S.; Papaemmanuil, E.; Penard-Lacronique, V.; Thakurta, A.; Vyas, P.; Levine, R.L. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood, 2017.
[http://dx.doi.org/10.1182/blood-2017-04-779447]
[188]
Stein, E.M.; DiNardo, C.D.; Pollyea, D.A.; Fathi, A.T.; Roboz, G.J.; Altman, J.K.; Stone, R.M.; DeAngelo, D.J.; Levine, R.L.; Flinn, I.W.; Kantarjian, H.M.; Collins, R.; Patel, M.R.; Frankel, A.E.; Stein, A.; Sekeres, M.A.; Swords, R.T.; Medeiros, B.C.; Willekens, C.; Vyas, P.; Tosolini, A.; Xu, Q.; Knight, R.D.; Yen, K.E.; Agresta, S.; de Botton, S.; Tallman, M.S. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia. Blood, 2017.
[http://dx.doi.org/10.1182/blood-2017-04-779405]

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