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.
Highlights
Resistance of tumor cells to apoptosis is a major obstacle in anticancer treatment
The strong increase of FITCAnnexin/PI double-positive cells 24 hours after treatment indicated a shift to late apoptosis/cell death at later time points (Fig. 1A)
Role of Bcl-2 proteins in DHA-induced apoptosis Because antiapoptotic Bcl-2 and Bcl-xL are known to suppress the activation of the intrinsic pathway, we investigated whether overexpression of these proteins would inhibit DHA-induced apoptosis
Summary
Resistance of tumor cells to apoptosis is a major obstacle in anticancer treatment. Current researches focus on the development of innovative compounds that increase the death of therapy-resistant tumor cells. Artemisinin and its semisynthetic derivatives are Authors' Affiliations: 1Institute of Cell Biology (Cancer Research), Department of Molecular Cell Biology, Medical School, University of Duisburg-Essen; 2Department of Hematology, University Hospital Essen, Essen, Germany; 3Department of Radiation Oncology, Experimental Radiation Oncology Group, University of Tübingen, Tübingen, Germany; 4Institute of Pharmaceutical Biotechnology, University of Applied Sciences, Biberach, Germany; and 5Department of Radiation Oncology, Ludwig-Maximilian University Munich, Munich, Germany. Note: Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Corresponding Author: Verena Jendrossek, Institute of Cell Biology, University of Duisburg Essen, Virchowstr.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.