anthricin and Stomach-Neoplasms

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.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Caspases; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Drugs, Chinese Herbal; Enzyme Activation; Female; G2 Phase Cell Cycle Checkpoints; Humans; M Phase Cell Cycle Checkpoints; Mice, Nude; Microtubules; Microvessels; Podophyllotoxin; Proto-Oncogene Proteins c-bcl-2; Stomach Neoplasms; Xenograft Model Antitumor Assays

Angiogenesis plays a critical role in the growth and metastasis of tumors, which makes it an attractive target for anti-tumor drug development. Deoxypodophyllotoxin (DPT), a natural product isolated from Anthriscus sylvestris, inhibits cell proliferation and migration in various cancer cell types. Our previous studies indicate that DPT possesses both anti-angiogenic and vascular-disrupting activities. Although the RhoA/ RhoA kinase (ROCK) signaling pathway is implicated in DPT-stimulated cytoskeleton remodeling and tumor vasculature suppressing, the detailed mechanisms by which DPT mediates these effects are poorly understood. In the current study, we found that DPT promotes cytoskeleton remodeling in human umbilical vein endothelial cells (HUVECs) via stimulation of AMP-activated protein kinase (AMPK) and that this effect is abolished by either treatment with a selective AMPK inhibitor or knockdown. Moreover, the cellular levels of LKB1, a kinase upstream of AMPK, were enhanced following DPT exposure. DPT-induced activation of AMPK in tumor vasculature effect was also verified by transgenic zebrafish (VEGFR2:GFP), Matrigel plug assay, and xenograft model in nude mice. The present findings may lay the groundwork for a novel therapeutic approach in treating cancer.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Angiogenesis Inhibitors; Animals; Animals, Genetically Modified; Cytoskeleton; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Enzyme Activation; Female; HeLa Cells; Human Umbilical Vein Endothelial Cells; Humans; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Neovascularization, Physiologic; Podophyllotoxin; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; rhoA GTP-Binding Protein; RNA Interference; Signal Transduction; Stomach Neoplasms; Time Factors; Transfection; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays; Zebrafish