Abstract
Abstract Clinical therapy resistance severely limits the efficacy of DNA damaging chemotherapy in human lung non-small cell lung carcinoma (NSCLC). Here we show that chemosensitization can be achieved in NSCLC by combining clinically-relevant DNA damaging agents with trifluoperazine (TFP). Colony formation assays demonstrated that TFP significantly potentiated the cytotoxicity of bleomycin and cisplatin in NSCLC cell lines. TFP impaired the repair of bleomycin- and cisplatin-induced DNA double strand breaks (DSBs), and consequently delayed the recovery from DNA damage-induced G2-M checkpoint (12 h vs at least 24 h). At later time points (> 24 h), NSCLC cells co-treated with TFP and bleomycin or cisplatin were able to overcome the initial G2-M checkpoint arrest, as evidenced by the reappearance of the mitosis markers and reduction in CFSE fluorescence. However, these cells showed increased micronucleation, apoptosis and gradual loss of proliferative capacity due to secondary G2-M arrest. Notably, TFP co-treated NSCLC cells underwent limited lysosomal membrane permeabilization (LMP) prior to Bak/Bax activation and mitochondrial depolarization. In turn this led to robust activation of caspase-3 preferentially in cells residing in the G2-M phase. In conclusion, our data supports the notion that by antagonizing DSB repair, TFP forces NSCLC cells into prolonged checkpoint arrest (whether initial or secondary) which sensitizes them to apoptosis associated with lysosomal dysfunction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2541. doi:10.1158/1538-7445.AM2011-2541
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call