Artemisinin dimer anticancer activity correlates with heme-catalyzed reactive oxygen species generation and endoplasmic reticulum stress induction
Correction(s) for this article
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Erratum: Artemisinin dimer anticancer activity correlates with heme-catalyzed reactive oxygen species generation and endoplasmic reticulum stress induction
- Luke H. Stockwin,
- Bingnan Han,
- Sherry X. Yu,
- Melinda G. Hollingshead,
- Mahmoud A. ElSohly,
- Waseem Gul,
- Desmond Slade,
- Ahmed M. Galal,
- Dianne L. Newton,
- Volume 127Issue 11International Journal of Cancer
- pages: E1-E1
- First Published online: May 6, 2010
Luke H. Stockwin
Developmental Therapeutics Program, SAIC-Frederick, NCI-Frederick, Frederick, MD
Search for more papers by this authorBingnan Han
Developmental Therapeutics Program, SAIC-Frederick, NCI-Frederick, Frederick, MD
Search for more papers by this authorSherry X. Yu
Developmental Therapeutics Program, SAIC-Frederick, NCI-Frederick, Frederick, MD
Search for more papers by this authorMelinda G. Hollingshead
Division of Cancer Treatment and Diagnosis, Developmental Therapeutics Program, NCI-Frederick, Frederick, MD
Search for more papers by this authorMahmoud A. ElSohly
ElSohly Laboratories, 5 Industrial Park Drive, Oxford, MS
National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS
Search for more papers by this authorWaseem Gul
ElSohly Laboratories, 5 Industrial Park Drive, Oxford, MS
Search for more papers by this authorDesmond Slade
National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS
Search for more papers by this authorAhmed M. Galal
National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS
Search for more papers by this authorCorresponding Author
Dianne L. Newton
Developmental Therapeutics Program, SAIC-Frederick, NCI-Frederick, Frederick, MD
Fax: +301-846-7021 or +301-846-6814.
Developmental Therapeutics Program, Building 320, Room 6, SAIC-Frederick, NCI-Frederick, Frederick, MD 21702, USASearch for more papers by this authorLuke H. Stockwin
Developmental Therapeutics Program, SAIC-Frederick, NCI-Frederick, Frederick, MD
Search for more papers by this authorBingnan Han
Developmental Therapeutics Program, SAIC-Frederick, NCI-Frederick, Frederick, MD
Search for more papers by this authorSherry X. Yu
Developmental Therapeutics Program, SAIC-Frederick, NCI-Frederick, Frederick, MD
Search for more papers by this authorMelinda G. Hollingshead
Division of Cancer Treatment and Diagnosis, Developmental Therapeutics Program, NCI-Frederick, Frederick, MD
Search for more papers by this authorMahmoud A. ElSohly
ElSohly Laboratories, 5 Industrial Park Drive, Oxford, MS
National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS
Search for more papers by this authorWaseem Gul
ElSohly Laboratories, 5 Industrial Park Drive, Oxford, MS
Search for more papers by this authorDesmond Slade
National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS
Search for more papers by this authorAhmed M. Galal
National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS
Search for more papers by this authorCorresponding Author
Dianne L. Newton
Developmental Therapeutics Program, SAIC-Frederick, NCI-Frederick, Frederick, MD
Fax: +301-846-7021 or +301-846-6814.
Developmental Therapeutics Program, Building 320, Room 6, SAIC-Frederick, NCI-Frederick, Frederick, MD 21702, USASearch for more papers by this authorAbstract
Analogs of the malaria therapeutic, artemisinin, possess in vitro and in vivo anticancer activity. In this study, two dimeric artemisinins (NSC724910 and 735847) were studied to determine their mechanism of action. Dimers were >1,000 fold more active than monomer and treatment was associated with increased reactive oxygen species (ROS) and apoptosis induction. Dimer activity was inhibited by the antioxidant L-NAC, the iron chelator desferroxamine and exogenous hemin. Similarly, induction of heme oxygenase (HMOX) with CoPPIX inhibited activity, whereas inhibition of HMOX with SnPPIX enhanced it. These results emphasize the importance of iron, heme and ROS in activity. Microarray analysis of dimer treated cells identified DNA damage, iron/heme and cysteine/methionine metabolism, antioxidant response, and endoplasmic reticulum (ER) stress as affected pathways. Detection of an ER-stress response was relevant because in malaria, artemisinin inhibits pfATP6, the plasmodium orthologue of mammalian sarcoplasmic/endoplasmic reticulum Ca2+-ATPases (SERCA). A comparative study of NSC735847 with thapsigargin, a specific SERCA inhibitor and ER-stress inducer showed similar behavior in terms of transcriptomic changes, induction of endogenous SERCA and ER calcium mobilization. However, thapsigargin had little effect on ROS production, modulated different ER-stress proteins and had greater potency against purified SERCA1. Furthermore, an inactive derivative of NSC735847 that lacked the endoperoxide had identical inhibitory activity against purified SERCA1, suggesting that direct inhibition of SERCA has little inference on overall cytotoxicity. In summary, these data implicate indirect ER-stress induction as a central mechanism of artemisinin dimer activity. © 2009 UICC
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