#2714, a novel active inhibitor with potent G2/M phase arrest and antitumor efficacy in preclinical models

Arresting cell cycle has been one of the most common approaches worldwide in Cancer therapy. Specifically, arresting cells in the G2/M phase is a promising therapeutic approach in the battle against lung Cancer. In the present study, we demonstrated the Anticancer activities and possible mechanism of compound #2714, which can prompt G2/M phase arrest followed by cell Apoptosis induction in Lewis lung carcinoma LL/2 cells. In vitro, #2714 significantly inhibited LL/2 cell viability in a concentration- and time-dependent manner while exhibiting few toxicities on non-cancer cells. The mechanism study showed that cell proliferation inhibition due to the treatment with #2714 correlated with G2/M phase arrest and was followed by LL/2 cell Apoptosis. The characterized changes were associated with the downregulation of phosphorylated cell division cycle 25C (Cdc25C) and upregulation of p53. Apoptosis-associated activation of cleaved Caspase-3 was also detected. Moreover, #2714 strongly attenuated LL/2 cell proliferation by disrupting the phosphorylation of p44/42 mitogen-activated protein kinase (MAPK). In vivo, intraperitoneal administration of #2714 (25-100 mg/kg/day) to mice bearing established tumors in xenograft models significantly prevented LL/2 tumor growth (58.1%) without detectable toxicity. Compound #2714 significantly increased Apoptosis in LL/2 lung Cancer cells in mice models, as observed via terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay, and the data from an immunohistochemical analysis showed that #2714 remarkably inhibited the proliferation and angiogenesis of lung Cancer in vivo. Taken together, our data suggest that #2714 has a high potential anti-lung Cancer efficacy with a pathway-specific mechanism of G2/M phase arrest and subsequent Apoptosis induction both in vitro and in vivo; its potential to be an Anticancer candidate warrants further investigation.