The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis
Language: 
English
Abstract: 

Recent research suggests that altered redox control of melanoma cell survival, proliferation, and invasiveness represents a chemical vulnerability that can be targeted by pharmacological modulation of cellular oxidative stress. The endoperoxide artemisinin and semisynthetic artemisinin-derivatives including dihydroartemisinin (DHA) constitute a major class of antimalarials that kill plasmodium parasites through induction of iron-dependent oxidative stress. Here, we demonstrate that DHA may serve as a redox chemotherapeutic that selectively induces melanoma cell apoptosis without compromising viability of primary human melanocytes. Cultured human metastatic melanoma cells (A375, G361, LOX) were sensitive to DHA-induced apoptosis with upregulation of cellular oxidative stress, phosphatidylserine externalization, and activational cleavage of procaspase 3. Expression array analysis revealed DHA-induced upregulation of oxidative and genotoxic stress response genes (GADD45A, GADD153, CDKN1A, PMAIP1, HMOX1, EGR1) in A375 cells. DHA exposure caused early upregulation of the BH3-only protein NOXA, a proapototic member of the Bcl2 family encoded by PMAIP1, and genetic antagonism (siRNA targeting PMAIP1) rescued melanoma cells from apoptosis indicating a causative role of NOXA-upregulation in DHA-induced melanoma cell death. Comet analysis revealed early DHA-induction of genotoxic stress accompanied by p53 activational phosphorylation (Ser 15). In primary human epidermal melanocytes, viability was not compromised by DHA, and oxidative stress, comet tail moment, and PMAIP1 (NOXA) expression remained unaltered. Taken together, these data demonstrate that metastatic melanoma cells display a specific vulnerability to DHA-induced NOXA-dependent apoptosis and suggest feasibility of future anti-melanoma intervention using artemisinin-derived clinical redox antimalarials.

Author(s): 
Cabello, Christopher M.
Lamore, Sarah D.
Bair, Warner B.
Qiao, Shuxi
Azimian, Sara
Lesson, Jessica L.
Wondrak, Georg T.
Item Type: 
Journal Article
Publication Title: 
Investigational New Drugs
Journal Abbreviation: 
Invest New Drugs
Publication Date: 
8/12/2015
Publication Year: 
2012
Pages: 
1289-1301
Volume: 
30
Issue: 
4
ISSN: 
1573-0646
DOI: 
10.1007/s10637-011-9676-7
Library Catalog: 
PubMed
Extra: 
PMID: 21547369 PMCID: PMC3203350

Turabian/Chicago Citation

Christopher M. Cabello, Sarah D. Lamore, Warner B. Bair, Shuxi Qiao, Sara Azimian, Jessica L. Lesson and Georg T. Wondrak. 8/12/2015. "The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis." Investigational New Drugs 30: 4: 1289-1301. 10.1007/s10637-011-9676-7.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1007/s10637-011-9676-7 | issn = 1573-0646 | volume = 30 | pages = 1289-1301 | last = Cabello | first = Christopher M. | coauthors = Lamore, Sarah D., Bair, Warner B., Qiao, Shuxi, Azimian, Sara, Lesson, Jessica L., Wondrak, Georg T. | title = The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis | journal = Investigational New Drugs | date = 8/12/2015 | pmid = | pmc = }} </ref>