BACKGROUND: Activating transcription factor 3 (ATF3), a stress-inducible gene, is a regulator of cisplatin-induced cytotoxicity, and enhancement of the ATF3 expression potentiates this cytotoxicity. MATERIALS AND METHODS: ATF3 expression and its binding to the transcription target CHOP were evaluated by western blot and chromatin immunoprecipitation (ChIP), respectively, in a panel of five cell lines (WI38, MCF7, PC3, A549). MTT assays were employed to assess the effects of many drugs, including disulfiram, on cell viability. RESULTS: ATF3 protein expression was up-regulated after cytotoxic doses of cisplatin treatment and it directly bound to the CHOP gene promoter, increasing this pro-apoptotic protein's expression. In a library screen of 1200 compounds, disulfiram, a dithiocarbamate drug, was identified as an enhancer of the cytotoxic effects of cisplatin. This increased cytotoxic action was synergistic and likely due to their ability to induce ATF3 independently. CONCLUSION: Understanding the role of ATF3 in cisplatin-induced cytotoxicity will lead to novel therapeutic approaches that could improve this drug's efficacy.
BACKGROUND:Activating transcription factor 3 (ATF3), a stress-inducible gene, is a regulator of cisplatin-induced cytotoxicity, and enhancement of the ATF3 expression potentiates this cytotoxicity. MATERIALS AND METHODS:ATF3 expression and its binding to the transcription target CHOP were evaluated by western blot and chromatin immunoprecipitation (ChIP), respectively, in a panel of five cell lines (WI38, MCF7, PC3, A549). MTT assays were employed to assess the effects of many drugs, including disulfiram, on cell viability. RESULTS:ATF3 protein expression was up-regulated after cytotoxic doses of cisplatin treatment and it directly bound to the CHOP gene promoter, increasing this pro-apoptotic protein's expression. In a library screen of 1200 compounds, disulfiram, a dithiocarbamate drug, was identified as an enhancer of the cytotoxic effects of cisplatin. This increased cytotoxic action was synergistic and likely due to their ability to induce ATF3 independently. CONCLUSION: Understanding the role of ATF3 in cisplatin-induced cytotoxicity will lead to novel therapeutic approaches that could improve this drug's efficacy.
Authors: M Mego; D Svetlovska; K Kalavska; P Lesko; M Makovník; J Obertova; Z Orszaghova; P Palacka; M Rečková; K Rejlekova; Sycova-Mila Z; J Mardiak; M Chovanec Journal: Invest New Drugs Date: 2022-06-28 Impact factor: 3.651
Authors: Richard E Kast; John A Boockvar; Ansgar Brüning; Francesco Cappello; Wen-Wei Chang; Boris Cvek; Q Ping Dou; Alfonso Duenas-Gonzalez; Thomas Efferth; Daniele Focosi; Seyed H Ghaffari; Georg Karpel-Massler; Kirsi Ketola; Alireza Khoshnevisan; Daniel Keizman; Nicolas Magné; Christine Marosi; Kerrie McDonald; Miguel Muñoz; Ameya Paranjpe; Mohammad H Pourgholami; Iacopo Sardi; Avishay Sella; Kalkunte S Srivenugopal; Marco Tuccori; Weiguang Wang; Christian R Wirtz; Marc-Eric Halatsch Journal: Oncotarget Date: 2013-04
Authors: Joanna Triscott; Cathy Lee; Kaiji Hu; Abbas Fotovati; Rachel Berns; Mary Pambid; Margaret Luk; Richard E Kast; Esther Kong; Eric Toyota; Stephen Yip; Brian Toyota; Sandra E Dunn Journal: Oncotarget Date: 2012-10