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J. Biol. Chem., Vol. 282, Issue 13, 9372-9382, March 30, 2007

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Evidence for the Involvement of Carbon-centered Radicals in the Induction of Apoptotic Cell Death by Artemisinin Compounds^*

Amy E. Mercer, James L. Maggs, Xiao-Ming Sun, Gerald M. Cohen, James Chadwick^¶, Paul M. O'Neill^¶, and B. Kevin Park¹

From the Department of Pharmacology and Therapeutics and the ^¶Department of Chemistry, the University of Liverpool, Liverpool L69 3GE and Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom

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 endoperoxides toward rapidly dividing human carcinoma cells and cell lines has been reported, and it is hypothesized that activation of the endoperoxide bridge by an iron(II) species, to form C-centered radicals, is essential for cytotoxicity. The studies described here have utilized artemisinin derivatives, dihydroartemisinin, 10-(p-bromophenoxy)dihydroartemisinin, and 10-(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. These studies have demonstrated the selective cytotoxic activity of the endoperoxides toward leukemia cell lines (HL-60 and Jurkat) over quiescent peripheral blood mononuclear cells. Deoxy-10-(p-fluorophenoxy)dihydroartemisinin, which lacks the endoperoxide bridge, was 50- and 130-fold less active in HL-60 and Jurkat cells, respectively, confirming the importance of this functional group for cytotoxicity. We have shown that chemical activation is responsible for cytotoxicity by using liquid chromatography-mass spectrometry analysis to monitor endoperoxide activation by measurement of a stable rearrangement product of endoperoxide-derived radicals, which was formed in sensitive HL-60 cells but not in insensitive peripheral blood mononuclear cells. In HL-60 cells the endoperoxides induce caspase-dependent apoptotic cell death characterized by concentration- and time-dependent mitochondrial membrane depolarization, activation of caspases-3 and -7, sub-G₀/G₁ DNA formation, and attenuation by benzyloxycarbonyl-VAD-fluoromethyl ketone, a caspase inhibitor. Overall, these results indicate that endoperoxide-induced cell death is a consequence of activation of the endoperoxide bridge to radical species, which triggers caspase-dependent apoptosis.

Received for publication, November 7, 2006 , and in revised form, January 16, 2007.

^* This work was supported in part by the Engineering and Physical Sciences Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, Sherrington Bldgs., University of Liverpool, Liverpool L69 3GE, UK. E-mail: b.k.park{at}liv.ac.uk.

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