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ownload sesquiterpene lactone dihydroartemisinin (DHA), a semisynthetic derivative of the herbal antimalaria rtemisinin, is cytotoxic to human tumor cells. Treatment of Jurkat T-lymphoma cells with DHA ina breakdown of the mitochondrial transmembrane potential, release of cytochrome c, activation of es, and DNA fragmentation indicative of apoptosis induction. Although the absence of FADD or e-8 did not alter apoptosis rates in Jurkat cells, overexpression of dominant-negative caspase-9 or of optotic Bcl-xL or Bcl-2 largely decreased the cytotoxicity of DHA, demonstrating a role of the intrinsic pathway. The proapoptotic Bcl-2 effector protein Bak and the Bcl-2 homology domain 3–only protein turned out to be important mediators of DHA-induced apoptosis in Jurkat cells. DHA treatment trigthe expression of NOXA and the activation of Bak. Furthermore, DHA-induced apoptosis was comabrogated by loss of Bak and largely reduced in cells with siRNA-mediated downregulation of Bak or . Proapoptotic signaling of DHA also involved the formation of reactive oxygen species and membrane ion. Pretreatment with the lipophilic radical scavenger vitamin E or the hydrophilic radical scavengers hione and N-acetylcysteine reduced DHA-induced membrane oxidation and apoptosis, respectively. tive changes also occurred in cells with disruption of the mitochondrial death pathway, suggesting a f reactive oxygen species and oxidative membrane changes in death signaling upstream of the mitoria. Interestingly, DHA increased the cytotoxic action of ionizing radiation and of the death receptor chond agonist tumor necrosis factor-related apoptosis-inducing ligand in Jurkat cells, suggesting a potential benefit of DHA in combined treatment strategies. Mol Cancer Ther; 9(9); 2497–510. ©2010 AACR.