Wortmannin sensitizes mammalian cells to radiation by inhibiting the DNA-dependent protein kinase-mediated rejoining of double-strand breaks

Wortmannin has been shown to be an efficient radiosensitizer, Since wortman nin is able to inhibit DNA-dependent protein kinase (DNA-PK) and double-str and break (DSB) rejoining, it is believed that its mechanism of radiation s ensitization is through the inhibition of DNA-PK-mediated repair of DSBs, H owever, since wortmannin is not a specific inhibitor, the possibility that other kinases are inhibited and thereby may contribute to radiosensitizatio n cannot be ruled out. Here we present data confirming the radiosensitizing effect of wortmannin on cells of different cell lines, In the same range o f wortmannin concentrations, survival after exposure to ionizing radiation correlated well with DSB rejoining and the induction of micronuclei, sugges ting that the inhibition of the processing of DSBs is involved in the sensi tizing effect. Pretreatment with wortmannin enhanced the radiosensitivity o f ataxia telangiectasia (AT) cells, thereby precluding the participation of ATM protein in the radiation sensitization by wortmannin, At the same time , irradiated DNA-PK-deficient cells were not significantly affected by pret reatment with wortmannin, These observations support a likely mechanism; th at is, wortmannin sensitizes cells to radiation through inhibition of the D NA-PK-mediated rejoining of DSBs. (C) 1999 by Radiation Research Society.