Antitumor and antiangiogenic effects of GA-13315, a gibberellin derivative.
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.
Zhang
Yanli
Y
Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650031, People's Republic of China.
Zhang
Hui
H
Chen
Jingbo
J
Zhao
Haixia
H
Zeng
Xianghui
X
Zhang
Hongbin
H
Qing
Chen
C
D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005875:Gibberellins / Q000494:pharmacology* / Q000633:toxicity; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007928:Lethal Dose 50; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D013792:Thalidomide / Q000494:pharmacology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C571876:13-chlorine-3,15-dioxy-gibberellic acid methyl ester; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D005875:Gibberellins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide; C007842:gibberellic acid