Effect of Metformin on ABCB1 and AMPK Expression in Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia

Summary

Acute lymphoblastic leukemia, is the most frequent cancer in children and adolescents. Some genes have been described to produce drug resistance, as ABCB1 probably by lack of activation of AMPK. Some manuscripts have shown that metformin has antitumoral activity, mainly by activation of AMPK. This is an experimental one center trial, that pretend analyze the effect of metformin at a dose of 1000mgm2 per day, on the expression of the ABCB1 and AMPK genes, when is added to conventional induction remission chemotherapy in newly diagnosed adolescents with acute lymphoblastic leukemia.

Timeline

Start

2021-02-09

Primary completion

2023-12

Completion

2023-12

Publications

• Background Smith MA, Seibel NL, Altekruse SF, Ries LA, Melbert DL, O'Leary M, Smith FO, Reaman GH. Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol. 2010 May 20;28(15):2625-34. doi: 10.1200/JCO.2009.27.0421. Epub 2010 Apr 19.
• Background Rivera-Luna R, Shalkow-Klincovstein J, Velasco-Hidalgo L, Cardenas-Cardos R, Zapata-Tarres M, Olaya-Vargas A, Aguilar-Ortiz MR, Altamirano-Alvarez E, Correa-Gonzalez C, Sanchez-Zubieta F, Pantoja-Guillen F. Descriptive Epidemiology in Mexican children with cancer under an open national public health insurance program. BMC Cancer. 2014 Oct 29;14:790. doi: 10.1186/1471-2407-14-790.
• Background Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, Reaman GH, Carroll WL. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol. 2012 May 10;30(14):1663-9. doi: 10.1200/JCO.2011.37.8018. Epub 2012 Mar 12.
• Background Wolfson JA, Richman JS, Sun CL, Landier W, Leung K, Smith EP, O'Donnell M, Bhatia S. Causes of Inferior Outcome in Adolescents and Young Adults with Acute Lymphoblastic Leukemia: Across Oncology Services and Regardless of Clinical Trial Enrollment. Cancer Epidemiol Biomarkers Prev. 2018 Oct;27(10):1133-1141. doi: 10.1158/1055-9965.EPI-18-0430. Epub 2018 Sep 27.
• Background Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 2001 Jul;11(7):1156-66. doi: 10.1101/gr.184901.
• Background Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006 Mar;5(3):219-34. doi: 10.1038/nrd1984.
• Background Rahgozar S, Moafi A, Abedi M, Entezar-E-Ghaem M, Moshtaghian J, Ghaedi K, Esmaeili A, Montazeri F. mRNA expression profile of multidrug-resistant genes in acute lymphoblastic leukemia of children, a prognostic value for ABCA3 and ABCA2. Cancer Biol Ther. 2014 Jan;15(1):35-41. doi: 10.4161/cbt.26603. Epub 2013 Oct 21.
• Background Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. Diabetes Care. 2010 Jul;33(7):1674-85. doi: 10.2337/dc10-0666.
• Background Trucco M, Barredo JC, Goldberg J, Leclerc GM, Hale GA, Gill J, Setty B, Smith T, Lush R, Lee JK, Reed DR. A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin. Pediatr Blood Cancer. 2018 Sep;65(9):e27224. doi: 10.1002/pbc.27224. Epub 2018 Jun 1.
• Background Leclerc GM, Leclerc GJ, Kuznetsov JN, DeSalvo J, Barredo JC. Metformin induces apoptosis through AMPK-dependent inhibition of UPR signaling in ALL lymphoblasts. PLoS One. 2013 Aug 23;8(8):e74420. doi: 10.1371/journal.pone.0074420. eCollection 2013.
• Background Dowling RJ, Niraula S, Stambolic V, Goodwin PJ. Metformin in cancer: translational challenges. J Mol Endocrinol. 2012 Mar 29;48(3):R31-43. doi: 10.1530/JME-12-0007. Print 2012 Jun.
• Background Kim HG, Hien TT, Han EH, Hwang YP, Choi JH, Kang KW, Kwon KI, Kim BH, Kim SK, Song GY, Jeong TC, Jeong HG. Metformin inhibits P-glycoprotein expression via the NF-kappaB pathway and CRE transcriptional activity through AMPK activation. Br J Pharmacol. 2011 Mar;162(5):1096-108. doi: 10.1111/j.1476-5381.2010.01101.x.

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