Deoxypodophyllotoxin induces G2/M cell cycle arrest and apoptosis in SGC-7901 cells and inhibits tumor growth in vivo.

Yu-Rong Wang,Bin Wang,Yuan Xu,Zhen-Zhou Jiang,Lu-Yong Zhang,Xiong Zhu,Mounia Guerram

doi:10.3390/molecules20011661

Abstract

Deoxypodophyllotoxin (DPT), a natural microtubule destabilizer, was isolated from Anthriscus sylvestris, and a few studies have reported its anti-cancer effect. However, the in vivo antitumor efficacy of DPT is currently indeterminate. In this study, we investigated the anti-gastric cancer effects of DPT both in vitro and in vivo. Our data showed that DPT inhibited cancer cell proliferation and induced G2/M cell cycle arrest accompanied by an increase in apoptotic cell death in SGC-7901 cancer cells. In addition, DPT caused cyclin B1, Cdc2 and Cdc25C to accumulate, decreased the expression of Bcl-2 and activated caspase-3 and PARP, suggesting that caspase-mediated pathways were involved in DPT-induced apoptosis. Animal studies revealed that DPT significantly inhibited tumor growth and decreased microvessel density (MVD) in a xenograft model of gastric cancer. Taken together, our findings provide a framework for further exploration of DPT as a novel chemotherapeutic for human gastric cancer.

Highlights

Gastric cancer is a leading cause of death worldwide, accounting for approximately 700,000 deaths per year
To further characterize the mechanism by which DPT induced G2/M cell cycle arrest, we examined the effects of DPT on the expression of cyclin B1, Cdc2 and Cdc25C proteins
Our results showed that DPT induced activation of caspase-3 which was accompanied by PARP cleavage, indicating that the caspase apoptotic pathway is involved in the mechanism of DPT-induced cell death

Summary

Introduction

Gastric cancer is a leading cause of death worldwide, accounting for approximately 700,000 deaths per year. Surgery is the mainstay of any curative treatment, recurrences and metastases are still observed in approximately two-thirds of patients [1]. As cell cycle progression approaches metaphase, microtubules are disrupted to form a mitotic spindle to facilitate chromosomal alignment on the metaphase plate. In this process, tubulin subunits freely exchange on the microtubules. If suchfree exchange of tubulin subunits is disrupted, the mitotic spindles will be compromised, interfering disturbing the cell division. Due to the clinical drug resistance observed in patients using anti-microtubule drugs, the discovery of new agents with optimal biopharmaceutical and pharmacological properties becomes the focus of numerous academic and industrial groups [7]

Results

Discussion

Conclusion