Inhibition of Serine Proteases by Anti-Inflammatory Triterpenoids

Abstract

The lupane triterpenoid lupeol, the ursane triterpenoid alpha-amyrin and esters of these compounds are present in the bark of roots of Alstonia boonei (Apocynaceae) and have anti-inflammatory properties. alpha-Amyrin is a competitive inhibitor of bovine trypsin and chymotrypsin (Ki values 29 microM and 18 microM, respectively). Lupeol linoleate, lupeol palmitate and alpha-amyrin linoleate are non-competitive inhibitors of trypsin (Ki values 7 microM, 10 microM and 16 microM, respectively). alpha-Amyrin linoleate is also a non-competitive inhibitor of chymotrypsin (Ki value 28 microM). Lupeol is a competitive inhibitor of both trypsin and chymotrypsin (Ki values 22 and 8 microM, respectively). alpha-Amyrin palmitate is a potent non-competitive inhibitor of chymotrypsin (Ki 6 microM). Lupeol, alpha-amyrin and the palmitic and linoleic acid esters of these compounds are ineffective or very weak as inhibitors of porcine pancreatic elastase and of Lucilia cuprina and Helicoverpa punctigera leucine aminopeptidases. These hydrophobic triterpenoids represent further examples of anti-inflammatory triterpenoids that are PKA inhibitors as well as being selective protease inhibitors.

Lupeol modulates NF-κB and PI3K/Akt pathways and inhibits skin cancer in CD-1 mice

“…Lupeol has been shown to possess strong anti-inflammatory, antiarthritic, antimutagenic and antimalarial activity in vitro and in vivo systems (Guevara et al, 1996;Geetha and Varalakshmi, 1999;Geetha and Varalakshmi, 2001;Ziegler et al, 2002). Lupeol has been shown to act as a potent inhibitor of protein kinases and serine proteases (Hasmeda et al, 1999;Rajic et al, 2000;Hodges et al, 2003) and inhibit the activity of DNA topoisomerase II, a target for anticancer chemotherapy (Moriarity et al, 1998;Wada et al, 2001). Lupeol has also been shown to improve the epidermal tissue reconstitution (Nikiema et al, 2001).…”

A Novel Dietary Triterpene Lupeol Induces Fas-Mediated Apoptotic Death of Androgen-Sensitive Prostate Cancer Cells and Inhibits Tumor Growth in a Xenograft Model

“…1), a triterpene found in fruits (such as olive, mango, strawberry, grapes, and figs), in many vegetables, and in several medicinal plants, is used in the treatment of various aliments worldwide by native people (18)(19)(20). Lupeol possesses strong antioxidant, anti-inflammatory, antiarthritic, antimutagenic, and antimalarial activity in vitro and in vivo systems; acts as a potent inhibitor of protein kinases and serine proteases; and inhibits the activity of DNA topoisomerase II, a target for anticancer chemotherapy (21)(22)(23)(24)(25)(26)(27). It has also been shown that Lupeol induces differentiation and inhibits the cell growth of mouse melanoma and human leukemia cells (28,29).…”

Anticancer Activity of an Indian Medicinal Plant, Alstonia scholaris, on Skin Carcinogenesis in Mice

“…24 It has been reported that A scholaris bark contains the alkaloids alstonidine, alstonin, alstovenine, chlorogenic acid, chlorogenine, ditain, ditaine, echicaoutchin, echicerin, echiretin, echitamine, echaitein, echitinin, echitin, porphyrine, porphyrosine, and reserpine. 5,25,26 Antioxidants act synergistically to counteract the deleterious effects of free radical-mediated LPO. SOD and CAT protect cells by catalyzing the harmful ROS such as O 2 -(SOD) and H 2 O 2 (CAT).…”

“…3,4 Epidemiological studies have indicated that the risk of cancer may be modified by changes in dietary habits. 5 Humans ingest a large number of naturally occurring antimutagens and anticarcinogens in food, which may inhibit one or more stages of carcinogenesis. 3 Several studies have indicated that compounds with antioxidants or anti-inflammatory properties as well as certain phytochemicals can inhibit tumor initiation, promotion, and progression in experimental animal models.…”