Methotrexate resistance is directly associated with glutathione concentration in acute lymphoblastic leukemia cell lines

• Grant number: 12/11952-0
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): September 01, 2012
• Effective date (End): July 31, 2016
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: José Andrés Yunes
• Grantee: Rafael Renatino Canevarolo
• Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil

Abstract

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in childhood. Methotrexate (MTX) is one of the main drugs used in treatment, whose mechanism of action is attributed to the inhibition of nucleotide synthesis - leading the leukemic blasts to apoptosis. However, some patients are resistant to treatment with MTX and may undergo a disease relapse; cure rates for these patients is markedly reduced. In our previous study, "interaction maps" built in silico revealed genes and proteins that appear to play a crucial role in the issue of resistance / sensitivity to MTX, making them potential targets for possible therapeutic intervention. Among such candidates is the nuclear factor kappa B (NF-kB), whose signaling pathway is involved in prosurvival, antiapoptotic and proliferative processes. Preliminary investigations have shown that some genes participants of the NF-kB signaling pathway are overexpressed in MTX-resistant ALL cell lines compared to MTX-sensitive cell lines. Similar results were found in MTX-poor responders ALL pediatric patients compared to -good responders. Through a reverse genetic approach by gene silencing and pharmacological inhibition of NF-kB components associated with the phenotype of resistance to MTX (IKBKB, REL, RELA and BIRC3) we intend to investigate the participation of each of these genes (and the NF-kB pathway as a whole) in the MTX-resistant phenotype acquisition in ALL cell lines, as well as the influence of each of this genes on the determination of the intracellular metabolome. Besides the preclinical intention of this work, aiming the sensitization of the cells to MTX, this will be the first study of the changes caused by gene silencing in the metabolome of ALL cells.

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

CANEVAROLO, Rafael Renatino. Methotrexate resistance is directly associated with glutathione concentration in acute lymphoblastic leukemia cell lines. 2017. Doctoral Thesis - Universidade Estadual de Campinas, Faculdade de Ciências Médicas.