Baghai, Tabassom2018-08-072018-08-072018-08-07http://hdl.handle.net/10393/37963http://dx.doi.org/10.20381/ruor-22221Lung cancer is the leading cause of cancer and cancer deaths worldwide, with non-small-cell lung carcinomas (NSCLC) representing 85% of all diagnosed lung cancers. Platinum-combination chemotherapy is the current standard treatment for NSCLC, however, associated toxicities and resistance limit its efficacy. Our laboratory previously identified activating transcription factor 3 (ATF3), a stress-inducible gene whose elevated and sustained expression can trigger apoptosis to a wide variety of stressors, as a key regulator of cisplatin cytotoxicity as well. Thus, enhanced and sustained induction of ATF3 by combining platins with other ATF3 inducers potentially represents an effective therapeutic strategy. A chemical library screen identified vorinostat and topotecan as ATF3 inducers that also enhance cisplatin cytotoxicity. ATF3 plays a significant role in cisplatin, vorinostat and topotecan and their combinations cytotoxicity. Importantly, vorinostat and topotecan induced synergistic cytotoxicity with cisplatin in NSCLC cell lines and their cisplatin resistance sub-lines with enhanced ATF3 expression observed. Our study suggests a potential novel therapeutic approach where ATF3 inducing agents in combination with platins represents a rational combination based therapeutic strategy.enCancer therapeuticsNSCLCCisplatinATF3Thesis