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Research Articles

The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non–small cell lung carcinoma cells to DNA double-strand break–induced cell death

¹ Unit of Medical Radiation Biology, Department of Oncology-Pathology, Cancer Centrum Karolinska and ² Unit for Analytical Toxicology, Department of Biosciences at Novum, Karolinska Institutet, Stockholm, Sweden; and ³ Division of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

Requests for reprints: Rolf Lewensohn, Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska Institutet, SE-171 76 Stockholm, Sweden. Phone: 46-8-51773188; Fax: 46-8-51771000. E-mail: Rolf.Lewensohn{at}ki.se

Abstract

Trifluoperazine (TFP), a member of the phenothiazine class of antipsychotic drugs, has been shown to augment the cytotoxicity of the DNA-damaging agent bleomycin. In the present study, we investigated the effect of trifluoperazine on (a) survival of bleomycin-treated human non–small cell lung carcinoma U1810 cells, (b) induction and repair of bleomycin-induced DNA strand breaks, and (c) nonhomologous end-joining (NHEJ), the major DNA double-strand break (DSB) repair pathway in mammalian cells. By using a clonogenic survival assay, we show here that concomitant administration of trifluoperazine at a subtoxic concentration enhances the cytotoxicity of bleomycin. Moreover, trifluoperazine also increases the longevity of bleomycin-induced DNA strand breaks in U1810 cells, as shown by both comet assay and fraction of activity released (FAR)-assay. This action seems to be related to suppression of cellular DNA DSB repair activities because NHEJ–mediated rejoining of DSBs occurs with significantly lower efficiency in the presence of trifluoperazine. We propose that TFP might be capable of inhibiting one or more elements of the DNA DSB repair machinery, thereby increasing the cytotoxicity of bleomycin in lung cancer cells. [Mol Cancer Ther 2007;6(8):2303–9]

Grant support: Swedish Cancer Society (R. Lewensohn and B. Stenerlöw), Stockholm Cancer Society (R. Lewensohn and K. Viktorsson), and Karolinska Institutet (R. Lewensohn and K. Viktorsson).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: A.G. Polischouk and Å. Holgersson contributed equally to this work.

Received 7/11/06; revised 6/ 2/07; accepted 6/29/07.