Evodiamine Induces G2/M Arrest and Apoptosis via Mitochondrial and Endoplasmic Reticulum Pathways in H446 and H1688 Human Small-Cell Lung Cancer Cells

Abstract

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.

Sinularin induces oxidative stress‐mediated G2/M arrest and apoptosis in oral cancer cells

“…Its apoptosis was based on annexin V/PI analysis and reached to about 20% for annexin V positive. In contrast, several drugs were reported to G2/M arrest and apoptosis without detectable subG1 accumulation, such as erianin in human osteosarcoma cells, evodiamine in lung cancer H446 and H1688 cells, withametelin in lung cancer A549 cells, and diarylpyrazole derivative (AM251) in A375 cells . Similarly, we found that sinularin induced G2/M arrest and apoptosis without detectable subG1 accumulation in oral cancer cell at 24 h treatment, where the apoptosis was confirmed by flow cytometry (annexin V/PI and pancaspase analyses) and western blotting (caspases 3, 8, 9, and PARP).…”

Evodiamine inhibits PDGF-BB-induced proliferation of rat vascular smooth muscle cells through the suppression of cell cycle progression and oxidative stress

“…Therefore, the observation that PDGF-BB increased and evodiamine decreased the expression of p21 in the present study was not unusual. Of note, the inhibitory effects of evodiamine on cell cycle progression have been previously observed in various human tumor cell lines, including small-cell lung cancer cells (20), gastric cancer cells (11), breast cancer cells (21), gastric adenocarcinoma cells (22) and cervical carcinoma HeLa cells (23), and are considered to be important in the antitumor action of evodiamine. The data obtained in the present study extends the current recognition of evodiamine, and suggested that the regulation of cell cycle progression by evodiamine may be general and function in a broader range of cell types, including tumor cells and vascular cells.…”

Tributyltin induces G2/M cell cycle arrest via NAD⁺-dependent isocitrate dehydrogenase in human embryonic carcinoma cells

“…Intracellular Ca 2+ may be also involved in mitochondrial dysfunction. Previous reports have shown that several anticancer drugs induce G2/M cell cycle arrest and apoptosis by depolarizing mitochondrial membrane potential and increasing intracellular Ca 2+ (Fang et al, 2014;Guo et al, 2014). With respect to intracellular Ca 2+ , there has been also reported that TBT induces mobilization of Ca 2+ from intracellular stores and results in phosphorylation of MAPKs because its suppression by chelation of intracellular Ca 2+ in human T lymphoblastoid cells (Yu et al, 2000).…”