Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines

Martin Michaelis , Malte C. Kleinschmidt , Susanne Barth , Florian Rothweiler , Janina Geiler , Rainer Breitling , Bernd Mayer , Hedwig Deubzer , Olaf Witt , Jörg Kreuter , Hans Wilhelm Doerr , Jaroslav Cinatl , Jindrich Cinatl

Artemisinin derivatives are well-tolerated anti-malaria drugs that also exert anti-cancer activity. Here, we investigated artemisinin and its derivatives dihydroartemisinin and artesunate in a panel of chemosensitive and chemoresistant human neuroblastoma cells as well as in primary neuroblastoma cultures. Only dihydroartemisinin and artesunate affected neuroblastoma cell viability with artesunate being more active. Artesunate induced apoptosis and reactive oxygen species in neuroblastoma cells. Of 16 cell lines and two primary cultures, only UKF-NB-3CDDP showed low sensitivity to artesunate. Characteristic gene expression signatures based on a previous analysis of artesunate resistance in the NCI60 cell line panel clearly separated UKF-NB-3CDDP from the other cell lines. L-Buthionine-S,R-sulfoximine, an inhibitor of GCL (glutamate-cysteine ligase), resensitised in part UKF-NB-3CDDP cells to artesunate. This finding together with bioinformatic analysis of expression of genes involved in glutathione metabolism showed that this pathway is involved in artesunate resistance. These data indicate that neuroblastoma represents an artesunate-sensitive cancer entity and that artesunate is also effective in chemoresistant neuroblastoma cells.

Mots clés: neuroblastoma; artesunate; artemisinin; chemoresistance; cancer; chemotherapy

Martin Michaelis, Malte C. Kleinschmidt, Susanne Barth, Florian Rothweiler, Janina Geiler, et al.. Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines. Biochemical Pharmacology, 2009, 79 (2), pp.130. ⟨10.1016/j.bcp.2009.08.013⟩. ⟨hal-00535826⟩