BCNU is a caspase-mediated inhibitor of drug-induced apoptosis

BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea], a bifunctional (alkylating/carbamoylating) anticancer agent, in noncytotoxic doses (12-50 microM) inhibited drug-induced apoptosis in HT58 human lymphoma cells exposed to etoposide (ETO; 50 microM) as well as in mouse thymocytes exposed to dexamethasone (...

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Published inCancer research (Chicago, Ill.) Vol. 58; no. 4; pp. 614 - 618
Main Authors PETAK, I, MIHALIK, R, BAUER, P. I, SÜLI-VARGHA, H, SEBESTYEN, A, KOPPER, L
Format Journal Article
LanguageEnglish
Published Philadelphia, PA American Association for Cancer Research 15.02.1998
Subjects
Antineoplastic agents
Antineoplastic Agents, Alkylating - pharmacology
Apoptosis - drug effects
Biological and medical sciences
Carmustine - pharmacology
Caspase 3
Caspases
Chemotherapy
Cysteine Endopeptidases - pharmacology
Dexamethasone - pharmacology
Etoposide - pharmacology
Humans
Lymphoma, B-Cell
Medical sciences
Pharmacology. Drug treatments
Tumor Cells, Cultured
Antineoplastic agent
Nitrosoureas
Cysteine endopeptidases
Glycosyltransferases
Carbamoylation
Lymphoproliferative syndrome
Established cell line
ADP-ribosyltransferase
Drug interaction
Tumor cell
Human
Corticosteroid
Drug combination
Dexamethasone
Enzyme
Thymocyte
Transferases
Carmustine
Etoposide
Malignant hemopathy
Non Hodgkin lymphoma
In vitro
NAD
Podophyllotoxine derivatives
Peptidases
Alkylating agent
Chemotherapy
Hydrolases
Pentosyltransferases
Apoptosis
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Summary:BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea], a bifunctional (alkylating/carbamoylating) anticancer agent, in noncytotoxic doses (12-50 microM) inhibited drug-induced apoptosis in HT58 human lymphoma cells exposed to etoposide (ETO; 50 microM) as well as in mouse thymocytes exposed to dexamethasone (5 microg/ml) in vitro in 4-h cultures. The cytoplasmic extracts of ETO-treated HT58 cells cleaved both purified poly(ADP-ribose)polymerase and Ac-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin fluorogenic caspase substrate, indicating the presence of active caspases, and these effects were inhibited by BCNU concentration dependently. The carbamoylating decomposite, 2-chloroethyl-isocyanate (6-25 microM), also decreased ETO-induced apoptosis in HT58 cells in vitro and their caspase 3-like activity ex vivo, whereas N-(2-chloroethyl)-N-nitrosocarbamoyl-valinamide, an alkylating and mainly intramolecularly carbamoylating nitrosourea derivative (400 microM), did not influence these phenomena. Furthermore, the activity of recombinant caspase 3 was also strongly inhibited by BCNU and 2-chloroethyl-isocyanate. These results indicate that BCNU, via its carbamoylating capacity, can inactivate cysteine protease(s) essential for ETO-induced apoptosis. This apoptosis-modulating property of BCNU, in turn, may influence the efficacy of chemotherapeutic protocols in the treatment of cancer.
ISSN:0008-5472
1538-7445