15357163mct100051-sup-supp_table_2.pdf (50.62 kB)
Supplementary Table 2 from Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway
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posted on 2023-03-31, 23:23 authored by René Handrick, Teona Ontikatze, Kerstin-Daniela Bauer, Florian Freier, Amelie Rübel, Jan Dürig, Claus Belka, Verena JendrossekSupplementary Table 2 from Dihydroartemisinin Induces Apoptosis by a Bak-Dependent Intrinsic Pathway
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ARTICLE ABSTRACT
The sesquiterpene lactone dihydroartemisinin (DHA), a semisynthetic derivative of the herbal antimalaria drug artemisinin, is cytotoxic to human tumor cells. Treatment of Jurkat T-lymphoma cells with DHA induced a breakdown of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases, and DNA fragmentation indicative of apoptosis induction. Although the absence of FADD or caspase-8 did not alter apoptosis rates in Jurkat cells, overexpression of dominant-negative caspase-9 or of antiapoptotic Bcl-xL or Bcl-2 largely decreased the cytotoxicity of DHA, demonstrating a role of the intrinsic death pathway. The proapoptotic Bcl-2 effector protein Bak and the Bcl-2 homology domain 3–only protein NOXA turned out to be important mediators of DHA-induced apoptosis in Jurkat cells. DHA treatment triggered the expression of NOXA and the activation of Bak. Furthermore, DHA-induced apoptosis was completely abrogated by loss of Bak and largely reduced in cells with siRNA-mediated downregulation of Bak or NOXA. Proapoptotic signaling of DHA also involved the formation of reactive oxygen species and membrane oxidation. Pretreatment with the lipophilic radical scavenger vitamin E or the hydrophilic radical scavengers glutathione and N-acetylcysteine reduced DHA-induced membrane oxidation and apoptosis, respectively. Oxidative changes also occurred in cells with disruption of the mitochondrial death pathway, suggesting a role of reactive oxygen species and oxidative membrane changes in death signaling upstream of the mitochondria. Interestingly, DHA increased the cytotoxic action of ionizing radiation and of the death receptor 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.Usage metrics
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Keywords
Cell CycleSignal transduction pathwaysCell Death And SenescenceCaspasesbcl-2 pathwaysDrug Discovery TechnologiesNatural productsDrug MechanismsCell cycle mechanisms of anticancer drug actionCellular responses to anticancer drugsDrug-mediated stimulation of cell death pathwaysDrug ResistanceReversal of drug resistanceSmall Molecule AgentsAlkylating agents
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