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Mechanisms of enhancement of cytotoxicity in etoposide and ionising radiation-treated cells by the protein kinase inhibitor wortmannin

Lookup NU author(s): Suzanne Kyle, Professor barbara Durkacz

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Abstract

We have investigated the effects of the protein kinase inhibitor wortmannin (WM) on the cytotoxic mechanisms of etoposide and ionising radiation (IR) in the Chinese hamster ovary K1 (CHO-K1) cell line, and its radiation-sensitive derivative, xrs-6, which is defective in DNA-dependent protein kinase (DNA-PK) function. WM potentiated the cytotoxicity of etoposide and IR in CHO-K1 cells approximately 1.6 and 3-fold, respectively, and this potentiation was abolished in xrs-6 cells, which were themselves more sensitive to etoposide and IR alone. WM partially inhibited the repair of etoposide-induced DNA double-strand breaks. Etoposide treatment caused a biphasic inhibition of DNA synthesis in both cell lines, and this was abrogated by co-incubation with WM. These data suggest that WM inhibits in intact cells both DNA-PK and either or both the ataxia telangiectasia (AT) and AT-related gene products ATM and ATR. (C) 2000 Elsevier Science Ltd.

Publication metadata

Author(s): Boulton, S., Kyle, S., Durkacz, B.W.

Publication type: Article

Publication status: Published

Journal: European Journal of Cancer

Year: 2000

Volume: 36

Issue: 4

Pages: 535-541

Print publication date: 01/03/2000

ISSN (print): 0959-8049

ISSN (electronic): 1359-6349

URL: http://dx.doi.org/10.1016/S0959-8049(99)00311-1

DOI: 10.1016/S0959-8049(99)00311-1

PubMed id: 10717533

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