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|Title:||Evidence for the involvement of carbon-centred radicals in the induction of apoptotic cell death by artemisinin compounds|
|Authors:||Mercer, Amy E.|
Maggs, James L.
Cohen, Gerald M.
O'Neill, Paul M.
Park, B. Kevin
|Publisher:||American Society for Biochemistry and Molecular Biology|
|Citation:||Journal of Biological Chemistry, 2007, 282(13), pp.9372-9382|
|Abstract:||Artemisinin and its derivatives are currently recommended as first-line antimalarials in regions where Plasmodium falciparum is resistant to traditional drugs. The cytotoxic activity of these compounds towards rapidly dividing human carcinoma cells and cell lines has been reported and it is hypothesised that activation of the endoperoxide bridge, by an iron (II) species, to form C-centred radicals, is essential for cytotoxicity. The studies described here have utilised artemisinin derivatives ; dihydroartemisinin, 10β-(p-bromophenoxy) dihydroartemisinin and 10β-(p-fluorophenoxy) dihydroartemisinin to determine the chemistry of endoperoxide bridge activation to reactive intermediates responsible for initiating cell death, and to elucidate the molecular mechanism of cell death. In vitro studies have demonstrated the selective cytotoxic activity of the endoperoxides toward leukaemia cell lines (HL-60 and Jurkat) over quiescent peripheral blood mononuclear cells (PBMC). Deoxy-10β-(p-fluorophenoxy) dihydroartemisinin, which lacks the peroxide bridge, was 50- to 130-fold less active in the same cells confirming the importance of this functional group for cytotoxicity. We have shown that chemical activation is responsible for cytotoxicity using LC-MS analysis to monitor endoperoxide bridge activation by measurement of a stable rearrangement product of endoperoxide-derived radicals, which was formed in sensitive HL-60 cells but not insensitive PBMC. In HL-60 cells the endoperoxides induce caspase-dependent apoptotic cell death; characterized by concentration- and time-dependent mitochondrial membrane depolarisation, activation of caspases-3 and –7, sub-G0/G1 DNA formation and attenuation by z-VAD.fmk, a caspase inhibitor. Overall, these results indicate that endoperoxide-induced cell death is a consequence of metabolic activation of the peroxide bridge to radical species, which trigger caspase-dependent apoptosis.|
|Description:||This is the authors' final draft of the paper published as Journal of Biological Chemistry, 2007, 282(13), pp.9372-9382. The definitive version is available from http://www.jbc.org/, doi:10.1074/jbc.M610375200|
|Appears in Collections:||Published Articles, MRC Toxicology Unit|
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