期刊
BMC SYSTEMS BIOLOGY
卷 4, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1752-0509-4-135
关键词
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资金
- Spanish Government: Ministerio de Ciencia e Innovacion [SAF2008-00164, SAF2005-04293, SAF2008-02251]
- Red Tematica de Investigacion Cooperativa en Cancer
- Instituto de Salud Carlos III
- Spanish Ministry of Science and Innovation
- European Regional Development Fund (ERDF) [RD06/0020/0046, RD06/0020/1037]
- Government of Catalonia [2009-SGR1308]
- European Commission [LSHG-CT-2006-037939, Health-F2-2008-202013, 222639]
- US National Institute of Health [1R01CA101199-01, 1R01CA118434-01A2]
- National Science Foundation [EPS-0447479]
- UCLA Center of Excellence [PO1 AT003960-01]
- Harbor-UCLA GCRC [MO1 RR00425-33]
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 C-13 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.
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