Antitumor and antiangiogenic effects of GA-13315, a gibberellin derivative.

Abstract

This study showed that 13-chlorine-3,15-dioxy-gibberellic acid methyl ester (GA-13315), a gibberellin derivative, possessed high antitumor and antiangiogenic activity in vitro and in vivo. Cytotoxicity assays showed that GA-13315 was a potential and efficient antitumor compound, with inhibitory concentration 50 (IC(50)) values ranging from 0.13 to 30.28 μg/ml in 12 human tumor cell lines, and it showed moderate toxicity to peripheral blood mononuclear cells with an IC(50) value of 14.2 μg/ml. Administration of 0.5 or 2.5 mg/kg GA-13315 for 23 days significantly inhibited tumor growth of human non-small cell lung tumor (A549) xenografts, with relative growth rates ranging from 29.91% to 35.05%. Acute toxicity was determined in ICR mice, and the lethal dose 50 (LD(50)) was 4.19 g/kg after intragastric administration. The high antitumor potency of GA-13315 occurred in parallel with its antiangiogenic activity. In vitro, GA-13315 inhibited recombinant human epithelial growth factor-induced chemotactic motility and capillary-like tube formation of primary cultured human endothelial cells. Furthermore, GA-13315 decreased the factor VIII(+) microvessel density and vascular endothelial growth factor expression in A549 tumors, indicating its antiangiogenic efficacy in vivo. These results indicate that the antiangiogenic activity of GA-13315 contributes to its anticancer properties. Further studies are needed to investigate the use of GA-13315 as an anticancer drug.

• Authors: Yanli Zhang, Hui Zhang, Jingbo Chen, Haixia Zhao, Xianghui Zeng, Hongbin Zhang, Chen Qing
• Journal: Investigational new drugs (Invest New Drugs) Vol. 30 Issue 1 Pg. 8-16 (Feb 2012) ISSN: 1573-0646 [Electronic] United States
• PMID: 20711631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 13-chlorine-3,15-dioxy-gibberellic acid methyl ester
• Angiogenesis Inhibitors
• Antineoplastic Agents
• Gibberellins
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Thalidomide
• gibberellic acid

Topics

• Angiogenesis Inhibitors (pharmacology, toxicity)
• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Carcinoma, Non-Small-Cell Lung (blood supply, drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chemotaxis (drug effects)
• Dose-Response Relationship, Drug
• Gibberellins (pharmacology, toxicity)
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• Inhibitory Concentration 50
• Lethal Dose 50
• Lung Neoplasms (blood supply, drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred ICR
• Neovascularization, Pathologic (metabolism, prevention & control)
• Neovascularization, Physiologic (drug effects)
• Thalidomide (pharmacology)
• Time Factors
• Tumor Burden (drug effects)
• Vascular Endothelial Growth Factor A (metabolism)
• Xenograft Model Antitumor Assays