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

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-sensi tive derivative, xrs-6, which is defective in DNA-dependent protein kinase (DNA-PK) function. WM potentiated the cytotoxicity of etoposide and IR in C HO-K1 cells approximately 1.6 and 3-fold, respectively, and this potentiati on was abolished in xrs-6 cells, which were themselves more sensitive to et oposide and IR alone. WM partially inhibited the repair of etoposide-induce d DNA double-strand breaks. Etoposide treatment caused a biphasic inhibitio n of DNA synthesis in both cell lines, and this was abrogated by co-incubat ion with WM. These data suggest that WM inhibits in intact cells both DNA-P K and either or both the ataxia telangiectasia (AT) and AT-related gene pro ducts ATM and ATR. (C) 2000 Elsevier Science Ltd. All rights reserved.