Background: 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.Results: 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.Conclusion: 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.
|Journal||BMC Systems Biology|
|State||Published - Oct 6 2010|
Bibliographical noteFunding Information:
This study was supported by Spanish Government: Ministerio de Ciencia e Innovación (SAF2008-00164, SAF2005-04293 and SAF2008-02251); from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation & European Regional Development Fund (ERDF) “Una manera de hacer Europa” (ISCIII-RTICC grants RD06/0020/0046 and RD06/0020/1037); government of Catalonia (2009-SGR1308) and European Commission (FP6, BioBridge LSHG-CT-2006-037939, FP7, Diaprepp Health-F2-2008-202013, Etherpath KBBE-grant agreement 222639). Additional support from the US National Institute of Health (grant # 1R01CA101199-01 and 1R01CA118434-01A2), National Science Foundation EPSCoR (grant # EPS-0447479) is acknowledged. Mass spectrometry facility was supported by grants to WNP Lee from UCLA Center of Excellence (PO1 AT003960-01) and from Harbor-UCLA GCRC (MO1 RR00425-33).
ASJC Scopus subject areas
- Structural Biology
- Modeling and Simulation
- Molecular Biology
- Computer Science Applications
- Applied Mathematics