Abstract
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.
Highlights
Lung cancer has become a common and major public health problem worldwide[1,2]
To measure the effect of #2714 on cell viability, a series of cancer cell lines was exposed to #2714 for 48 h and cell viability was detected via Cell Counting Kit-8 (CCK-8) assay
Research has indicated that chemotherapy causes poor effects on the survival rate of patients with advanced lung cancer, notwithstanding that it was used as the clinical first-line treatment strategies for patients with advanced lung cancers[20]
Summary
Lung cancer has become a common and major public health problem worldwide[1,2]. Lung cancers have been ranked as number one in causes of cancer-related disease and deaths[3,4]. The survival status of lung cancer is very poor;[5,6] the dismal 5-year survival rate has risen. The use of chemosynthetic small molecular targeted drugs has shown to be effective in treating lung cancer[10,11,12]. Over the past few years, we have been trying to find new candidates for lung cancer treatment and have reported several small molecule candidates for lung cancer therapy via computer-aided drug design (CADD). Using our Official journal of the Cell Death Differentiation Association
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