The goal of this study was to evaluate the ability of EVO to decrease cell viability and promote cell cycle arrest and apoptosis in small cell lung cancer (SCLC) cells. Lung cancer has the highest incidence and mortality rates among all cancers. Chemotherapy is the primary treatment for SCLC; however, the drugs that are currently used for SCLC are less effective than those used for non-small cell lung cancer (NSCLC). Therefore, it is necessary to develop new drugs to treat SCLC. In this study, the effects of evodiamine (EVO) on cell growth, cell cycle arrest and apoptosis were investigated in the human SCLC cell lines NCI-H446 and NCI-H1688. The results represent the first report that EVO can significantly inhibit the viability of both H446 and H1688 cells in dose- and time-dependent manners. EVO induced cell cycle arrest at G2/M phase, induced apoptosis by up-regulating the expression of caspase-12 and cytochrome C protein, and induced the expression of Bax mRNA and by down-regulating of the expression of Bcl-2 mRNA in both H446 and H1688 cells. However, there was no effect on the protein expression of caspase-8. Taken together, the inhibitory effects of EVO on the growth of H446 and H1688 cells might be attributable to G2/M arrest and subsequent apoptosis, through mitochondria-dependent and endoplasmic reticulum stress-induced pathways (intrinsic caspase-dependent pathways) but not through the death receptor-induced pathway (extrinsic caspase-dependent pathway). Our findings suggest that EVO is a promising novel and potent antitumor drug candidate for SCLC. Furthermore, the cell cycle, the mitochondria and the ER stress pathways are rational targets for the future development of an EVO delivery system to treat SCLC.
Lymph node metastasis is still an important issue in metastatic process of lung adenocarcinoma. C-C chemokine receptor 7 (CCR7) has been proved to be closely associated with the metastasis of lung adenocarcinoma, and the mechanism is poorly understood. In order to investigate the relationship between CCR7 and lymph node metastasis in lung adenocarcinoma, and to explore the role of CCR7 in treating lung adenocarcinoma, 40 clinical specimens were collected to define the relationship between CCR7 and lymph node metastasis in lung adenocarcinoma by immunohistochemistry. The siRNA was used to suppress CCR7 expression in A549 cells. The scratch test, transwell test, qRT-PCR, western blot, flow cytometry and immunofluorescence were used to investigate the lymph node metastasis-related function of CCR7
in vitro
. The athymic mice subcutaneous injection was used to research lung adenocarcinoma formation
in vivo
. Clinical case studies show that higher expression of CCR7 in lung adenocarcinoma tissues was associated with a higher lymph node metastasis. Inhibition of expression of CCR7 can reduce the migration and invasion and suppress the expression of VEGF-C, VEGF-D and VEGF-R3
in vitro
and
in vivo
. Moreover, CCR7 silence also suppressed WNT and p-ERK pathways
in vitro
. All the results indicate that CCR7 can promote lymph node metastasis in lung adenocarcinoma by regulating VEGF-C/D-R3 pathway. Thus CCR7 is proposed to be a potential prediction for poor prognosis of lung adenocarcinoma, and a therapeutic target for lymph node metastasis.
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