Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer.

Abstract

STAT3 has been strongly implicated in human malignancies, and constitutive activation of STAT3 serves a crucial role in cell survival, angiogenesis, immune evasion, and inflammation. In this study, we showed that nitidine chloride, a natural phytochemical alkaloid derived from Zanthoxylum nitidum (Roxb) DC, exerts potent anticancer activity through STAT3 signaling cascade. Nitidine chloride dose dependently suppressed VEGF-induced endothelial cell proliferation, migration, and tubular structure formation in vitro and dramatically reduced VEGF-triggered neovascularization in mouse cornea and Matrigel plugs in vivo. This angiogenesis inhibition mediated by nitidine chloride was well interpreted by the suppression of Janus kinase 2/STAT3 signaling and STAT3 DNA-binding activity in endothelial cells. Furthermore, nitidine chloride suppressed the constitutively activated STAT3 protein, its DNA-binding activity, and the expression of STAT3-dependent target genes, including cyclin D1, Bcl-xL, and VEGF in human gastric cancer cells. Consistent with the earlier findings, nitidine chloride inhibited gastric tumor cell growth and induced tumor cell apoptosis in vitro and effectively suppressed the volume, weight, and microvessel density of human SGC-7901 gastric solid tumors (n = 8) at a dosage of 7 mg/kg/d (intraperitoneal injection). Immunohistochemistry and Western blot analysis further revealed that the expression of STAT3, CD31, and VEGF protein in xenografts was remarkably decreased by the alkaloid. Taken together, we propose that nitidine chloride is a promising anticancer drug candidate as a potent STAT3 signaling inhibitor.

• Authors: Jing Chen, Jieqiong Wang, Lei Lin, Lijun He, Yuanyuan Wu, Li Zhang, Zhengfang Yi, Yihua Chen, Xiufeng Pang, Mingyao Liu
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 2 Pg. 277-87 (Feb 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22203730 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzophenanthridines
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Vascular Endothelial Growth Factor A
• nitidine

Topics

• Animals
• Apoptosis (drug effects)
• Benzophenanthridines (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism, physiology)
• Humans
• Immunohistochemistry
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• Neovascularization, Pathologic (pathology, prevention & control)
• Neovascularization, Physiologic (drug effects)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Tumor Burden (drug effects)
• Vascular Endothelial Growth Factor A (metabolism, pharmacology)
• Xenograft Model Antitumor Assays