TY - JOUR
T1 - Promising effects of the 4HPR-BSO combination in neuroblastoma monolayers and spheroids
AU - Cuperus, Roos
AU - Van Kuilenburg, André B.P.
AU - Leen, René
AU - Bras, Johannes
AU - Caron, Huib N.
AU - Tytgat, Godelieve A.M.
N1 - Funding Information:
This study was supported by the Stichting Kindergeneeskundig Kankeronderzoek.
PY - 2011/9/15
Y1 - 2011/9/15
N2 - To enhance the efficacy of fenretinide (4HPR)-induced reactive oxygen species (ROS) in neuroblastoma, 4HPR was combined with buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, in neuroblastoma cell lines and spheroids, the latter being a three-dimensional tumor model. 4HPR exposure (2.5-10 μM, 24 h) resulted in ROS induction (114-633%) and increased GSH levels (68-120%). A GSH depletion of 80% of basal levels was observed in the presence of BSO (25-100 μM, 24 h). The 4HPR-BSO combination resulted in slightly increased ROS levels (1.1- to 1.3-fold) accompanied by an increase in cytotoxicity (110-150%) compared to 4HPR treatment alone. A correlation was observed between the ROS-inducing capacity of each cell line and the increase in cytotoxicity induced by 4HPR-BSO compared to 4HPR. No significant correlation between baseline antioxidant levels and sensitivity to 4HPR or BSO was observed. In spheroids, 4HPR-BSO induced a strong synergistic growth retardation and induction of apoptosis. Our data show that BSO increased the cytotoxic effects of 4HPR in neuroblastoma monolayers and spheroids in ROS-producing cell lines. This indicates that the 4HPR-BSO combination might be a promising new strategy in the treatment of neuroblastoma.
AB - To enhance the efficacy of fenretinide (4HPR)-induced reactive oxygen species (ROS) in neuroblastoma, 4HPR was combined with buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, in neuroblastoma cell lines and spheroids, the latter being a three-dimensional tumor model. 4HPR exposure (2.5-10 μM, 24 h) resulted in ROS induction (114-633%) and increased GSH levels (68-120%). A GSH depletion of 80% of basal levels was observed in the presence of BSO (25-100 μM, 24 h). The 4HPR-BSO combination resulted in slightly increased ROS levels (1.1- to 1.3-fold) accompanied by an increase in cytotoxicity (110-150%) compared to 4HPR treatment alone. A correlation was observed between the ROS-inducing capacity of each cell line and the increase in cytotoxicity induced by 4HPR-BSO compared to 4HPR. No significant correlation between baseline antioxidant levels and sensitivity to 4HPR or BSO was observed. In spheroids, 4HPR-BSO induced a strong synergistic growth retardation and induction of apoptosis. Our data show that BSO increased the cytotoxic effects of 4HPR in neuroblastoma monolayers and spheroids in ROS-producing cell lines. This indicates that the 4HPR-BSO combination might be a promising new strategy in the treatment of neuroblastoma.
KW - Buthionine sulfoximine
KW - Fenretinide
KW - Free radicals
KW - Glutathione
KW - Neuroblastoma
KW - Reactive oxygen species
KW - Spheroids
UR - http://www.scopus.com/inward/record.url?scp=80051783761&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2011.06.019
DO - 10.1016/j.freeradbiomed.2011.06.019
M3 - Article
C2 - 21741474
AN - SCOPUS:80051783761
SN - 0891-5849
VL - 51
SP - 1213
EP - 1220
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 6
ER -