Abstract
Introduction: metformin, antidiabetic drug evaluated in several in vitro and in vivo cancer models, is able of increasing the adenosine monophosphate activated protein kinase and block tumor signaling pathways. Objetive: to evaluate the antitumor effects of metformin in MOLT-4 cell line and in patients under treatment for remission induction. Materials and methods: in vitro phase: essay in MOLT-4 cell line adding metformin 40 mM evaluating the viability and cell cycle by flow cytometry. Clinic phase: Case-control study in patients with de novo acute lymphoblastic leukemia, adding metformin three time a day on pretreatment stage and remission induction, against the historical record of the institutional protocol HGMLAL07. Statistical analysis: chi-square analysis, multivariate analysis for risk factors and evaluation of the effect over the remission by Odds ratio. Results: celular assay: metformina inhibited cell viability at 120 hours reducing the percentage of cells in phase S. Clinical assay: 151 patients were studied, 29.1% on metformina arm. The highest rate of good steroid response and complete remissions were found in patients who received metformin (59,1% versus 26,2% and 81,8% vs 57,9%) statistically significant (p= 0.000* and 0.006, 95% IC). Conclusions: the addition of metformin to chemotherapy increased the good steroids response to steroids and rates of complete remissions. In vitro, and similar to other models, metformin arrest cells in G0/G1, inducing a decrease in cell viability. MÉD.UIS. 2015;28(5):221-8.
References
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. World Health Organization; 2008.
Nath SV, Nicholson I, Tapp H, Zola H, Zannettino AC, Revesz T. Reticulin fibres anchor leukaemic blasts in the marrow of patients with acute lymphoblastic leukaemia. Med Hypotheses. 2011;77(3):333-5
Hillman RS, Ault KA, Leporrier M, Rinder HM. The acute myeloid leukemias. Hematology in Clinical Practice. 5th ed. New York: McGraw-Hill; 2010. p. 215–28.
Jabbour E, O’Brien S, Konopleva M, Kantarjian H. New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia. Cancer. 2015. Doi: 10.1002/cncr.29383.
World Healt Organization[Internet]. International Agency for Research on Cancer. Lyon, France. Globocan 2012: Estimated Cancer Incidence, Mortality, and Prevalence Worldwide in 2012. 2015; [citado 15 Mar 2015]. Disponible en: http://globocan.iarc.fr/ Default.aspx.
Hurtado-Monroy R, Solano-Estrada B, Vargas-Viveros P. Leucemia para el médico general. Rev Fac Med Univ Nac Auton Mex. 2012;55(2):11-25.
Rabin KR, Poplack DG. Management strategies in acute lymphoblastic leukemia. Oncology (Willist. Park). 2011;25(4):328-35.
Arteaga-Ortiz L, Buitrón-Santiago N, Rosas-López A, Rosas-Arzate G, Armengolt-Jiménez A, Aguayo A, et al. Acute lymphoblastic leukemia: experience in adult patients treated with hyperCVAD and 0195 Protocol, at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Cohort 2003-2007. Rev Invest
Clin. 2008;60(6):459-69.
Ramos C, Rozen E, León M, Martínez TA, Olarte I, Catellanos H, et al. Results of treatment of acute lymphoblastic leukemia in two cohorts of Mexican patients. Rev Med Chil. 2011;139(9):1135–42.
Pathak P, Hess R, Weiss MA. Liposomal vincristine for relapsed or refractory Ph-negative acute lymphoblastic leukemia: a review of literature. Ther Adv Hematol. 2014;5(1):18–24.
Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013;381(9881):1943–55.
Onciu M. Acute lymphoblastic leukemia. Hematol Oncol Clin North Am. 2009;23(4):655–74.
Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood.
;106(12):3760–7.
Kantarjian H, Thomas D, O’Brien S, Cortes J, Giles F, Jeha S, et al. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004;101(12):2788–801.
Papanas N, Maltezos E, Mikhailidis DP. Metformin and cancer: licence to heal? Expert Opin Investig Drugs. 2010;19(8):913–7.
Emami A, Fisel P, Nies AT, Schaeffeler E, Schwab M. Metformin and cancer: from the old medicine cabinet to pharmacological pitfalls and prospects. Trends Pharmacol Sci. 2013;34(2):126–35.
Rattan R, Ali Fehmi R, Munkarah A. Metformin: an emerging new therapeutic option for targeting cancer stem cells and metastasis. J Oncol. 2012;2012:1-12.
Van der Heijden MS, Bernards R. Inhibition of the PI3K pathway: hope we can believe in? Clin Cancer Res. 2010;16(12):3094–9.
Dowling RJ, Niraula S, Stambolic V, Goodwin PJ. Metformin in cancer: translational challenges. J Mol Endocrinol. 2012;48(3):R31–43.
Cufi S, Corominas-Faja B, Vazquez-Martin A, Oliveras-Ferraros C, Dorca J, Bosch-Barrera J, et al. Metformin-induced preferential killing of breast cancer initiating CD44+CD24-/low cells is sufficient to overcome primary resistance to trastuzumab
in HER2+ human breast cancer xenografts. Oncotarget.2012;3(4):395–8.
Bonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gonzaga A, et al. Dual Effect of Metformin on Breast Cancer Proliferation in a Randomized Presurgical Trial. J Clin Oncol. 2012;30(21):2593–600.
Chan DK, Miskimins WK. Metformin and phenethyl isothiocyanate combined treatment in vitro is cytotoxic to ovarian cancer cultures. J Ovarian Res. 2012;5(1):19.
Wu B, Li S, Sheng L, Zhu J, Gu L, Shen H, et al. Metformin inhibits the development and metastasis of ovarian cancer. Oncol Rep. 2012;28(3):903–8.
Grisouard J, Dembinski K, Mayer D, Keller U, Müller B, ChristCrain M. Targeting AMP-activated protein kinase in adipocytes to modulate obesity-related adipokine production associated with insulin resistance and breast cancer cell proliferation. Diabetol Metab Syndr. 2011;3:16.
Bánhegyi RJ, Rus-Gal PO, Nagy AK, Martyin T, Wágner R, Varga R, et al. Antidiabetic therapy-a new possibility in the complex therapy of cancer? Magy Onkol. 2010;54(4):315–23.
McNeer JL, Nachman JB. The optimal use of steroids in paediatric acute lymphoblastic leukaemia: no easy answers. Br J Haematol. 2010;149(5):638–52.
Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, et al. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002;99(3):863–71.
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) [Internet]. 2010 [cited 2015 May 3].
Disponible in: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
Shah DS, Kumar R. Steroid resistance in leukemia. World J Exp Med. 2013;3(2):21–5.
Friedmann AM, Weinstein HJ. The role of prognostic features in the treatment of childhood acute lymphoblastic leukemia. Oncologist. 2000;5(4):321-8.
Zhao L, Wen ZH, Jia CH, Li M, Luo SQ, Bai XC. Metformin induces G1 cell cycle arrest and inhibits cell proliferation in nasopharyngeal carcinoma cells. Anat Rec (Hoboken). 2011;294(8):1337–43.
Luo Q, Hu D, Hu S, Yan M, Sun Z, Chen F. In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma. BMC Cancer. 2012;12:517.
Suissa S, Azoulay L. Metformin and cancer: mounting evidence against an association. Diabetes Care. 2014;37(7):1786–8.
Del Barco S, Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, et al. Metformin: multi-faceted protection against cancer. Oncotarget. 2011;2(12):896–917.
Shin J, Wang S, Deng W, Wu J, Gao J, Zhong XP. Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function. Proc Natl Acad Sci U S A. 2014;111(8):776–83.
Maciolek J, Pasternak J, Wilson H. Metabolism of activated T lymphocytes. Curr Opin Immunol. 2014;27:60-74.
Huai L, Wang C, Zhang C, Li Q, Chen Y, Jia Y, et al. Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway. Biochem Biophys Res Commun. 2012;422(3):398–404.
Pan J, Chen C, Jin Y, Fuentes-Mattei E, Velazquez-Tores G, Benito JM, et al. Differential impact of structurally different antidiabetic drugs on proliferation and chemosensitivity of acute lymphoblastic leukemia cells. Cell Cycle. 012;11(12):2314–26.
Cornell R, Palmer J. Adult acute leukemia. Dis Mon. 2012;58(4):219–38.
Honjo S, Ajani J, Scott A, Chen Q, Skinner H, Stroehlein J, et al. Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer. Int J Oncol. 2014;45(2):567–74.
Sandulache V, Yang L, Skinner H. Use of biguanides to improve response to chemotherapy. Methods Mol Biol. 2014;1165:3–9.
Morgillo F, Sasso F, Della Corte C, Vitagliano D, D’Aiuto E, Troiani T, et al. Synergistic effects of metformin treatment in combination with gefitinib, a selective EGFR tyrosine kinase inhibitor, in LKB1 wild-type NSCLC cell lines. Clin Cancer Res. 2013;19(13):3508–19.