Evodiamine induces G2/M arrest and apoptosis via mitochondrial and endoplasmic reticulum pathways in H446 and H1688 human small-cell lung cancer cells.

Chunshu Fang,Jingqing Zhang,Qunyou Tan,Ling Liu,Xiaoqing Fan,Jianchun Luo,Di Qi,Irina V Lebedeva

doi:10.1371/journal.pone.0115204

Chunshu Fang, Jingqing Zhang + Show 6 more

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https://doi.org/10.1371/journal.pone.0115204

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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.

Highlights

Lung cancer is the most common form of cancer, accounting for 12.5% of all annual newly diagnosed cancer cases worldwide
Our results indicated that the inhibitory effects of EVO on the growth of H446 and H1688 cells were attributable to G2/M arrest and subsequent apoptosis through the mitochondria-dependent and endoplasmic reticulum (ER) stress-induced caspase activation pathways but not through the death receptorinduced caspase activation pathway
(2) EVO inhibited H1688 growth in a time-dependent manner at concentrations ranging from 1.25 mM to 10 mM within 48 h and at a concentration of 20 mM within 72 h. (3) The inhibition rates after treatment for 48 h were almost the same as those after 72 h of treatment with EVO at concentrations ranging from 1.25 mM to 10 mM. (4) The IC50 values of EVO in H1688 cells decreased from 8.14 mM to 2.08 mM or 1.37 mM

Summary

Introduction

Lung cancer is the most common form of cancer, accounting for 12.5% of all annual newly diagnosed cancer cases worldwide. SCLC is distinguished from NSCLC by rapid tumor growth and widespread metastasis. According to the guidelines of the American Cancer Society [2], chemotherapy is the main treatment for SCLC, and cisplatin, etoposide, carboplatin and irinotecan are the most frequently used drugs. These drugs have only limited efficacy and cause severe side effects [3]. The five-year survival rate for SCLC is rather low (3,8%) compared to the five-year survival rate for all forms of lung cancer (,15%) [4]. Novel and effective antitumor drugs with fewer and less severe side effects are urgently needed to improve the clinical outcomes

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