Overexpression of acid sphingomyelinase sensitizes glioma cells to chemotherapy.
Ceramide has been shown by many studies to induce apoptosis. Therefore, upregulation of ceramide is discussed as a novel approach for tumor treatment. However, it is unknown whether overexpression of acid sphingomyelinase releasing ceramide from sphingomyelin sensitizes cells to chemotherapy and, thus, serves as a potential target to amplify chemotherapy. Here, the authors demonstrate that transfection of human or murine glioma cells with acid sphingomyelinase results in a marked sensitization of glioma cells to gemcitabine and doxorubicin, respectively. Transfected cells responded to chemotherapy with an increased activation of acid sphingomyelinase, elevated ceramide levels, and approximately fourfold higher rates of cell death than control transfected cells. Neutralization of reactive oxygen species prevented these events. The data indicate a significant sensitization of glioma cells to chemotherapy treatment by expression of acid sphingomyelinase and further suggest an activation of acid sphingomyelinase by gemcitabine or doxorubicin, respectively, via reactive oxygen species.
Grammatikos
Georgios
G
Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
Teichgräber
Volker
V
Carpinteiro
Alexander
A
Trarbach
Tanja
T
Weller
Michael
M
Hengge
Ulrich R
UR
Gulbins
Erich
E
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma; D006801:Humans; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D002518:Ceramides; D003841:Deoxycytidine; D004317:Doxorubicin; D013108:Sphingomyelin Phosphodiesterase; D000093542:Gemcitabine