Bcl-2 overexpression decreases BCNU sensitivity of a human glioblastoma line through enhancement of catalase activity.
The aim of this study was to evaluate the role of bcl-2 in 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) sensitivity of the ADFS human glioblastoma cell line in vitro and in vivo. To this end, the ADFS line expressing a low level of the bcl-2 protein was transfected with a bcl-2 expression vector. We found that bcl-2 overexpressing clones were less sensitive to in vitro BCNU treatment than the control clone. Cell cycle analysis demonstrated that while BCNU induced a consistent block in S/G2-M phases of the cell cycle in the control clone, it did not affect the cell cycle phase distribution of the two bcl-2 transfectants. The different sensitivity to BCNU was unrelated to the ability of bcl-2 to inhibit apoptosis, while bcl-2 appeared to protect bcl-2 transfectants from BCNU toxicity through an increase of catalase activity. The ability of the catalase inhibitor, sodium azide, to increase the BCNU sensitivity of the bcl-2 transfectants to levels of the BCNU-treated control clone substantiated the role of the catalase activity. The effect of bcl-2 in reducing sensitivity to BCNU was also confirmed by in vivo experiments. Xenografts of bcl-2 overexpressing tumors were less sensitive to BCNU treatment than xenografts originating from control cells.
Del Bufalo
D
D
Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Experimental Research Center, Rome, Italy. delbufalo@ifo.it
Trisciuoglio
D
D
Biroccio
A
A
Marcocci
L
L
Buglioni
S
S
Candiloro
A
A
Scarsella
M
M
Leonetti
C
C
Zupi
G
G
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis; D002330:Carmustine / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism*; D002453:Cell Cycle; D003432:Cross-Linking Reagents / Q000494:pharmacology; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D019253:Proto-Oncogene Proteins c-bcl-2; D002374:Catalase; D002330:Carmustine