The inhibition of angiogenesis and tumor growth by denbinobin is associated with the blocking of insulin-like growth factor-1 receptor signaling.

Abstract

Denbinobin, which is a phenanthraquinone derivative present in the stems of Ephemerantha lonchophylla, has been demonstrated to display antitumor activity. Recent reports suggest that the enhanced activity of insulin-like growth factor-1 receptor (IGF-1R) is closely associated with tumor angiogenesis and growth. This study aims at investigating the roles of denbinobin in suppressing these effects and at further elucidating the underlying molecular mechanisms. In the present study, we used an in vivo xenograft model antitumor and the Matrigel implant assays to show that denbinobin suppresses lung adenocarcinoma A549 growth and microvessel formation. Additionally, crystal violet and capillary-like tube formation assays indicated that denbinobin selectively inhibits insulin-like growth factor-1 (IGF-1)-induced proliferation (GI50=1.3×10⁻⁸ M) and tube formation of human umbilical vascular endothelial cells (HUVECs) without influencing the effect of epidermal growth factor; vascular endothelial growth factor and basic fibroblast growth factor. Furthermore, denbinobin inhibited the IGF-1-induced migration of HUVECs in a concentration-dependent fashion. Western blotting and immunoprecipitation demonstrated that denbinobin causes more efficient inhibition of IGF-1-induced activation of IGF-1R and its downstream signaling targets, including , extracellular signal-regulated kinase, Akt, mTOR, p70S6K, 4EBP and cyclin D1. All of our results provide evidences that denbinobin suppresses the activation of IGF-1R and its downstream signaling pathway, which leads to the inhibition of angiogenesis. Our findings suggest that denbinobin may be a novel IGF-1R kinase inhibitor and has potential therapeutic abilities for angiogenesis-related diseases such as cancer.

• Authors: An-Chi Tsai, Shiow-Lin Pan, Chin-Yu Lai, Chih-Ya Wang, Chien-Chih Chen, Chien-Chang Shen, Che-Ming Teng
• Journal: The Journal of nutritional biochemistry (J Nutr Biochem) Vol. 22 Issue 7 Pg. 625-33 (Jul 2011) ISSN: 1873-4847 [Electronic] United States
• PMID: 20951021 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Anthraquinones
• Antineoplastic Agents, Phytogenic
• Phenanthrenes
• denbinobin
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1

Topics

• Animals
• Anthraquinones (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Humans
• Insulin-Like Growth Factor I (antagonists & inhibitors, metabolism)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neovascularization, Pathologic (drug therapy)
• Phenanthrenes (pharmacology)
• Receptor, IGF Type 1 (drug effects, metabolism)
• Signal Transduction (drug effects)