Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines.
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-3(r)CDDP(1000) 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-3(r)CDDP(1000) from the other cell lines. l-Buthionine-S,R-sulfoximine, an inhibitor of GCL (glutamate-cysteine ligase), resensitised in part UKF-NB-3(r)CDDP(1000) 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.
Michaelis
Martin
M
Institut für Medizinische Virologie, Klinikum der J.W. Goethe-Universität, Paul Ehrlich-Strasse 40, 60596 Frankfurt am Main, Germany.
Kleinschmidt
Malte C
MC
Barth
Susanne
S
Rothweiler
Florian
F
Geiler
Janina
J
Breitling
Rainer
R
Mayer
Bernd
B
Deubzer
Hedwig
H
Witt
Olaf
O
Kreuter
Jörg
J
Doerr
Hans Wilhelm
HW
Cinatl
Jaroslav
J
Cinatl
Jindrich
J
D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D018384:Oxidative Stress
D037621:Artemisinins; D000077332:Artesunate