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.