The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non small cell lung carcinoma cells to DNA double-strand break induced cell death.
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.
Polischouk
Anya G
AG
Unit of Medical Radiation Biology, Department of Oncology-Pathology, Cancer Centrum Karolinska, Stockholm, Sweden.
Holgersson
Asa
A
Zong
Dali
D
Stenerlöw
Bo
B
Karlsson
Hanna L
HL
Möller
Lennart
L
Viktorsson
Kristina
K
Lewensohn
Rolf
R
D014150:Antipsychotic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D011995:Recombination, Genetic / Q000187:drug effects; D014268:Trifluoperazine / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
D014150:Antipsychotic Agents; D001761:Bleomycin; D014268:Trifluoperazine