Betulinic acid inhibits growth factor-induced in vitro angiogenesis via the modulation of mitochondrial function in endothelial cells.
Betulinic acid (BetA), a pentacyclic triterpene, is a selective apoptosis-inducing agent that works directly in mitochondria. Recent study has revealed that BetA inhibits in vitro enzymatic activity of aminopeptidase N (APN, EC 3.4.11.2), which is known to play an important role in angiogenesis, but the anti-angiogenic activity of BetA has not been reported yet. Data presented here show that BetA potently inhibited basic fibroblast growth factor (bFGF)-induced invasion and tube formation of bovine aortic endothelial cells (BAECs) at a concentration which had no effect on the cell viability. To access whether the anti-angiogenic nature of BetA originates from its inhibitory action against aminopeptidase N (APN) activity, the effect of BetA on APN was investigated. Surprisingly, BetA did not inhibit in vivo APN activity in endothelial cells or APN-positive tumor cells. On the other hand, BetA significantly decreased the mitochondrial reducing potential, and treatment with mitochondrial permeability transition (MPT) inhibitors attenuated BetA-induced inhibition of endothelial cell invasion. These results imply that anti-angiogenic activity of BetA occurs through a modulation of mitochondrial function rather than APN activity in endothelial cells.
Kwon
Ho Jeong
HJ
Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, Seoul 143-747, Korea. kwonhj@sejong.ac.kr
Shim
Joong Sup
JS
Kim
Jin Hee
JH
Cho
Hyun Young
HY
Yum
Young Na
YN
Kim
Seung Hee
SH
Yu
Jaehoon
J
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001011:Aorta / Q000166:cytology*; D018826:CD13 Antigens / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003094:Collagen / Q000494:pharmacology; D004396:Coloring Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006133:Growth Substances / Q000378:metabolism*; D007797:Laminin / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D053978:Pentacyclic Triterpenes; D010539:Permeability; D011509:Proteoglycans / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology*; D000094062:Betulinic Acid
D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D004338:Drug Combinations; D006133:Growth Substances; D007797:Laminin; D053978:Pentacyclic Triterpenes; D011509:Proteoglycans; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; D014315:Triterpenes; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen; D018826:CD13 Antigens; C022616:thiazolyl blue; D000094062:Betulinic Acid