Anti-tumor activity of oridonin on SNU-5 subcutaneous xenograft model via regulation of c-Met pathway

• Published in: Tumor biology 2014-09, Vol.35 (9), p.9139-9146
• Main Authors: Liu, Hua, Qian, Changlin, Shen, Zhiyong
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell adhesion & migration; Cell Line, Tumor; Cell Proliferation - drug effects; Diterpenes, Kaurane - chemistry; Diterpenes, Kaurane - pharmacology; Dose-Response Relationship, Drug; Female; Humans; Immunoblotting; Immunohistochemistry; Inhibitory Concentration 50; Ki-67 Antigen - metabolism; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - prevention & control; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-met - metabolism; Research Article; Signal Transduction - drug effects; Skin & tissue grafts; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1007/s13277-014-2178-4

Gastric cancer is the leading cause of cancer death worldwide. Oridonin, a diterpenoid isolated from Rabdosia rubescens , has attracted considerable attention as a potential treatment for gastric cancer based on its anti-tumor effects in many tumor cell lines. However, detailed anti-tumor mechanisms of oridonin remain a matter of speculation. In the present study, a gastric carcinoma cell line harboring c-Met gene amplification SNU-5 was used to investigate the underlying mechanisms. The results showed that in vitro, oridonin potently inhibited c-Met phosphorylation and c-Met-dependent cell proliferation (IC50 value, 36.8 μM), meanwhile down-regulated the expression of the downstream signaling molecules including phospho-c-Raf, phospho-Erk, and phospho-Akt. In vivo, oridonin showed efficacy at well-tolerated doses, including marked cytoreductive anti-tumor activity in SNU-5 subcutaneous xenograft model. The anti-tumor efficacy of oridonin was dose-dependent and showed strong inhibition of c-Met phosphorylation. Additional mechanism of action studies showed dose-dependent inhibition of c-Met-dependent signal transduction, tumor cell proliferation (Ki67), and reduction of microvessel density (CD31). These results suggested that the anti-tumor activity of oridonin may be mediated by direct effects on tumor cell growth or survival as well as anti-angiogenic mechanisms. In summary, the results indicated that oridonin exerted anti-tumor growth on human gastric cancer SNU-5 in vitro and in vivo by direct regulation of c-Met signaling pathway and the anti-tumor effects was mainly based on its anti-proliferation and anti-angiogenesis.