Edelfosine-induced metabolic changes in cancer cells that precede the overproduction of reactive oxygen species and apoptosis
- Equal contributors
1 Department of Biochemistry and Molecular Biology, Faculty of Biology, Institute of Biomedicine of University of Barcelona (IBUB) and IDIBAPS, Unit Associated with CSIC, 08028 Barcelona, Spain
2 A.N.Belozersky Institute of Physico-Chemical Biology, Moscow State University, 199899 Moscow, Russia
3 Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (C.S.I.C.)-Universidad de Salamanca. E-37007 Salamanca, Spain
4 Department of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY 40292, USA
5 Department of Medicine, Structural Biology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
6 Department of Pediatrics, Research and Education Institute, Harbor-UCLA Medical Center, 90502 Torrance, California, USA
7 Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
BMC Systems Biology 2010, 4:135 doi:10.1186/1752-0509-4-135Published: 6 October 2010
Metabolic flux profiling based on the analysis of distribution of stable isotope tracer in metabolites is an important method widely used in cancer research to understand the regulation of cell metabolism and elaborate new therapeutic strategies. Recently, we developed software Isodyn, which extends the methodology of kinetic modeling to the analysis of isotopic isomer distribution for the evaluation of cellular metabolic flux profile under relevant conditions. This tool can be applied to reveal the metabolic effect of proapoptotic drug edelfosine in leukemia Jurkat cell line, uncovering the mechanisms of induction of apoptosis in cancer cells.
The study of 13C distribution of Jukat cells exposed to low edelfosine concentration, which induces apoptosis in ≤5% of cells, revealed metabolic changes previous to the development of apoptotic program. Specifically, it was found that low dose of edelfosine stimulates the TCA cycle. These metabolic perturbations were coupled with an increase of nucleic acid synthesis de novo, which indicates acceleration of biosynthetic and reparative processes. The further increase of the TCA cycle fluxes, when higher doses of drug applied, eventually enhance reactive oxygen species (ROS) production and trigger apoptotic program.
The application of Isodyn to the analysis of mechanism of edelfosine-induced apoptosis revealed primary drug-induced metabolic changes, which are important for the subsequent initiation of apoptotic program. Initiation of such metabolic changes could be exploited in anticancer therapy.