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01-07-2015 | Original Article

The mechanism of synergistic effects of arsenic trioxide and rapamycin in acute myeloid leukemia cell lines lacking typical t(15;17) translocation

Authors: Vilma Dembitz, Hrvoje Lalic, Alen Ostojic, Radovan Vrhovac, Hrvoje Banfic, Dora Visnjic

Published in: International Journal of Hematology | Issue 1/2015

Abstract

Arsenic trioxide (ATO) has potent clinical activity in the treatment of patients with acute promyelocytic leukemia (APL), but is much less efficacious in acute myeloid leukemia (AML) lacking t(15;17) translocation. Recent studies have indicated that the addition of mammalian target of rapamycin (mTOR) inhibitors may increase the sensitivity of malignant cells to ATO. The aim of the present study was to test for possible synergistic effects of ATO and rapamycin at therapeutically achievable doses in non-APL AML cells. In HL-60 and U937 cell lines, the inhibitory effects of low concentrations of ATO and rapamycin were synergistic and more pronounced in U937 cells. The combination of drugs increased apoptosis in HL-60 cells and increased the percentage of cells in G₀/G₁ phase in both cell lines. In U937 cells, rapamycin alone increased the activity of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and the addition of ATO decreased the level of phosphorylated ERK, Ser473 phosphorylated Akt and anti-apoptotic Mcl-1 protein. Primary AML cells show high sensitivity to growth-inhibitory effects of rapamycin alone or in combination with ATO. The results of the present study reveal the mechanism of the synergistic effects of two drugs at therapeutically achievable doses in non-APL AML cells.

Chen SJ, Zhou GB, Zhang XW, Mao JH, de Thé H, Chen Z. From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia. Blood. 2011;117:6425–37.PubMedCentralPubMedCrossRef

Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–21.PubMedCrossRef

de Thé H, Le Bras M, Lallemand-Breitenbach V. The cell biology of disease: acute promyelocytic leukemia, arsenic, and PML bodies. J Cell Biol. 2012;198:11–21.PubMedCentralPubMedCrossRef

Nasr R, Guillemin MC, Ferhi O, Soilihi H, Peres L, Berthier C, et al. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med. 2008;14:1333–42.PubMedCrossRef

Dai J, Weinberg RS, Waxman S, Jing Y. Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood. 1999;93:268–77.PubMed

McCollum G, Keng PC, States JC, McCabe MJ Jr. Arsenite delays progression through each cell cycle phase and induces apoptosis following G2/M arrest in U937 myeloid leukemia cells. J Pharmacol Exp Ther. 2005;313:877–87.PubMedCrossRef

Stępnik M, Ferlińska M, Smok-Pieniążek A, Gradecka-Meesters D, Arkusz J, Stańczyk M. Assessment of the involvement of oxidative stress and mitogen-activated protein kinase signaling pathways in the cytotoxic effects of arsenic trioxide and its combination with sulindac or its metabolites: sulindac sulfide and sulindac sulfone on human leukemic cell lines. Med Oncol. 2012;29:1161–72.PubMedCrossRef

Ramos AM, Fernández C, Amrán D, Sancho P, de Blas E, Aller P. Pharmacologic inhibitors of PI3K/Akt potentiate the apoptotic action of the antileukemic drug arsenic trioxide via glutathione depletion and increased peroxide accumulation in myeloid leukemia cells. Blood. 2005;105:4013–20.PubMedCrossRef

Wetzler M, Andrews C, Ford LA, Tighe S, Barcos M, Sait SN, et al. Phase 1 study of arsenic trioxide, high-dose cytarabine, and idarubicin to down-regulate constitutive signal transducer and activator of transcription 3 activity in patients aged <60 years with acute myeloid leukemia. Cancer. 2011;117:4861–8.PubMedCrossRef

10.

Wang R, Xia L, Gabrilove J, Waxman S, Jing Y. Downregulation of Mcl-1 through GSK-3β activation contributes to arsenic trioxide-induced apoptosis in acute myeloid leukemia cells. Leukemia. 2013;27:315–24.PubMedCentralPubMedCrossRef

11.

Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014;13:140–56.PubMedCentralPubMedCrossRef

12.

Récher C, Beyne-Rauzy O, Demur C, Chicanne G, Dos Santos C, Mas VM, et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood. 2005;105:2527–34.PubMedCrossRef

13.

Wall M, Poortinga G, Hannan KM, Pearson RB, Hannan RD, McArthur GA. Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation. Blood. 2008;112:2305–17.PubMedCrossRef

14.

Iwanami A, Gini B, Zanca C, Matsutani T, Assuncao A, Nael A, et al. PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. Proc Natl Acad Sci USA. 2013;110:4339–44.PubMedCentralPubMedCrossRef

15.

Liu N, Tai S, Ding B, Thor RK, Bhuta S, Sun Y, et al. Arsenic trioxide synergizes with everolimus (Rad001) to induce cytotoxicity of ovarian cancer cells through increased autophagy and apoptosis. Endocr Relat Cancer. 2012;19:711–23.PubMedCrossRef

16.

Guilbert C, Annis MG, Dong Z, Siegel PM, Miller WH Jr, Mann KK. Arsenic trioxide overcomes rapamycin-induced feedback activation of AKT and ERK signaling to enhance the anti-tumor effects in breast cancer. PLoS One. 2013;8(12):e85995.PubMedCentralPubMedCrossRef

17.

Altman JK, Yoon P, Katsoulidis E, Kroczynska B, Sassano A, Redig AJ, et al. Regulatory effects of mammalian target of rapamycin-mediated signals in the generation of arsenic trioxide responses. J Biol Chem. 2008;283:1992–2001.PubMedCrossRef

18.

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;20:941–51.PubMedCrossRef

19.

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;17:645–56.PubMedCrossRef

20.

Lalic H, Lukinovic-Skudar V, Banfic H, Visnjic D. Rapamycin enhances dimethyl sulfoxide-mediated growth arrest in human myelogenous leukemia cells. Leuk Lymph. 2012;53:2253–61.CrossRef

21.

Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70:440–6.PubMedCrossRef

22.

Dalton WT Jr, Ahearn MJ, McCredie KB, Freireich EJ, Stass SA, Trujillo JM. Hl-60 cell line was derived from a patient with FAB-M2 and not FAB-M3. Blood. 1988;71:242–7.PubMed

23.

Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118:3065–74.PubMedCentralPubMed

24.

Tamburini J, Chapuis N, Bardet V, Park S, Sujobert P, Willems L, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood. 2008;111:379–82.PubMedCrossRef

25.

Mills JR, Hippo Y, Robert F, Chen SM, Malina A, Lin CJ, Trojahn U, Wendel HG, Charest A, Bronson RT, Kogan SC, Nadon R, Housman DE, Lowe SW, Pelletier J. mTORC1 promotes survival through translational control of Mcl-1. Proc Natl Acad Sci USA. 2008;105:10853–8.PubMedCentralPubMedCrossRef

26.

Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, Cai X, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood. 1997;89:3345–53.PubMed

27.

Nishioka C, Ikezoe T, Yang J, Nishioka C, Ikezoe T, Yang J, et al. 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;125:1710–20.PubMedCrossRef

28.

Lalic H, Dembitz V, Lukinovic-Skudar V, Banfic H, Visnjic D. 5-Aminoimidazole-4-carboxamide ribonucleoside induces differentiation of acute myeloid leukemia cells. Leuk Lymph. 2014;55:2375–83.CrossRef

29.

Verges B, Walter T, Cariou B. Endocrine side effects of anti-cancer drugs: effects of anti-cancer targeted therapies on lipid and glucose metabolism. Eur J Endocrinol. 2014;170:R43–55.PubMedCrossRef

30.

Suganuma K, Miwa H, Imai N, Shikami M, Gotou M, Goto M, et al. Energy metabolism of leukemia cells: glycolysis versus oxidative phosphorylation. Leuk Lymph. 2010;51:2112–9.CrossRef

31.

Sims JT, Plattner R. MTT assays cannot be utilized to study the effects of STI571/Gleevec on the viability of solid tumor cell lines. Cancer Chemother Pharmacol. 2009;64:629–33.PubMedCentralPubMedCrossRef

32.

Wang X, Yue P, Kim YA, Fu H, Khuri FR, Sun S. Enhancing mammalian target of rapamycin (mTOR)-targeted cancer therapy by preventing mTOR/Raptor inhibition-initiated, mTOR/Rictor-independent Akt activation. Cancer Res. 2008;68:7409–18.PubMedCentralPubMedCrossRef

33.

Zeng Z, Sarbassov DD, Samudio IJ, Yee KWL, Munsell MF, Jackson CE, et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit Akt activation i AML. Blood. 2007;109:3509–12.PubMedCentralPubMedCrossRef

34.

Altman JK, Sassano A, Kaur S, Glaser H, Kroczynska B, Redig AJ, et al. Dual mTORC2/mTORC1 targeting results in potent suppressive effectson acute myeloid leukemia (AML) progenitors. Clin Cancer Res. 2011;17:4378–88.PubMedCentralPubMedCrossRef

35.

Sánchez Y, Simón GP, Calviño E, de Blas E, Aller P. Curcumin stimulates reactive oxygen species production and potentiates apoptosis induction by the antitumor drugs arsenic trioxide and lonidamine in human myeloid leukemia cell lines. J Pharmacol Exp Ther. 2010;335:114–23.PubMedCrossRef

36.

Ramirez-Valle F, Badura ML, Braunstein S, Narasimhan M, Schneider RJ. Mitotic raptor promotes mTORC1 activity, G(2)/M cell cycle progression, and internal ribosome entry site-mediated mRNA translation. Mol Cell Biol. 2010;30:3151–64.PubMedCentralPubMedCrossRef

37.

Johnson DE. Src family kinases and the MEK/ERK pathway in the regulation of myeloid differentiation and myeloid leukemogenesis. Adv Enzyme Regul. 2008;48:98–112.PubMedCentralPubMedCrossRef

38.

Biggs JR, Ahn NG, Kraft AS. Activation of the mitogen-activated protein kinase pathway in U937 leukemic cells induces phosphorylation of the amino terminus of the TATA-binding protein. Cell Growth Differ. 1998;9:667–76.PubMed

39.

Kandilci A, Grosveld GC. SET-induced calcium signaling and MAPK/ERK pathway activation mediate dendritic cell-like differentiation of U937 cells. Leukemia. 2005;19:1439–45.PubMedCrossRef

40.

Yan H, Peng ZG, Wu YL, Jiang Y, Yu Y, Huang Y, et al. Hypoxia-simulating agents and selective stimulation of arsenic trioxide-induced growth arrest and cell differentiation in acute promyelocytic leukemic cells. Haematologica. 2005;90:1607–16.PubMed

41.

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;29:582–8.PubMedCrossRef

42.

Yang J, Ikezoe T, Nishioka C, Ni L, Koeffler HP, Yokoyama A. Inhibition of mTORC1 by RAD001 (everolimus) potentiates the effect of 1,25-dihydroxyvitamin D₃ to induce growth arrest and differentiation of AML cells in vitro and in vivo. Exp Hematol. 2010;38:666–76.PubMedCrossRef

43.

Mercalli A, Calavita I, Dugnani E, Citro A, Cantarelli E, Nano R, et al. Rapamycin unbalances the polarization of human macrophages to M1. Immunology. 2013;140:179–90.PubMedCentralPubMedCrossRef

44.

Hackstein H, Taner T, Logar AJ, Thomson AW. Rapamycin inhibits macropinocytosis and mannose receptor-mediated endocytosis by bone marrow-derived dendritic cells. Blood. 2002;100:1084–7.PubMedCrossRef

Title: The mechanism of synergistic effects of arsenic trioxide and rapamycin in acute myeloid leukemia cell lines lacking typical t(15;17) translocation
Authors: Vilma Dembitz
Hrvoje Lalic
Alen Ostojic
Radovan Vrhovac
Hrvoje Banfic
Dora Visnjic
Publication date: 01-07-2015
Publisher: Springer Japan
Published in: International Journal of Hematology / Issue 1/2015
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI: https://doi.org/10.1007/s12185-015-1776-2

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