Naturally occurring proteasome inhibitors from mate tea (Ilex paraguayensis) serve as models for topical proteasome inhibitors.
Proteasome inhibitors have emerged as a clinically important therapy for neoplastic disease, with velcade, an organoboron compound used extensively in multiple myeloma. Recently, (-)-epigallocatechin gallate has been found to be a potent inhibitor of the proteasomal chymotrypsin-like activity. Other compounds that inhibit angiogenesis and are active as chemopreventive agents, such as curcumin, also inhibit proteasome activity. We have screened natural product extracts using ras-transformed endothelial cells (SVR cells) as a bioassay, and found that extracts of mate tea (Ilex paraguayensis) inhibit the growth of these endothelial cells. The extract was fractionated and found to have novel cinnamate esters that inhibit proteasome activity. Based upon the structures of the compounds isolated from mate tea, we examined synthetic analogs of these compounds for proteasome activity. Cinnamic acid amides had no inhibitory activity against proteasomes, whereas cinnamate esters displayed the activity. Based upon these findings, preclinical and clinical trials of topical cinnamate esters as proteasome inhibitors are warranted for psoriasis and other inflammatory disorders.
Arbiser
Jack L
JL
Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. jarbise@emory.edu
Li
Xing-Cong
XC
Hossain
Chowdhury Fiaz
CF
Nagle
Dale G
DG
Smith
David M
DM
Miller
Paul
P
Govindarajan
Baskaran
B
DiCarlo
Josh
J
Landis-Piwowar
Kristin R
KR
Dou
Q Ping
QP
D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002726:Chlorogenic Acid / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D002934:Cinnamates / Q000737:chemistry* / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D030019:Ilex paraguariensis / Q000737:chemistry*; D019169:Jurkat Cells; D019906:Nuclear Magnetic Resonance, Biomolecular; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology; D061988:Proteasome Inhibitors
D002934:Cinnamates; D004952:Esters; D010936:Plant Extracts; D061988:Proteasome Inhibitors; D002726:Chlorogenic Acid