A dicyanotriterpenoid induces cytoprotective enzymes and reduces multiplicity of skin tumors in UV-irradiated mice.
Inducible phase 2 enzymes constitute a primary line of cellular defense. The oleanane dicyanotriterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile (TP-225) is a very potent inducer of these systems. Topical application of TP-225 to SKH-1 hairless mice increases the levels of NAD(P)H-quinone acceptor oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1) and protects against UV radiation-induced dermal thickening. Daily topical treatments of 10 nmol of TP-225 to the backs of mice that were previously subjected to low-level chronic UVB radiation (30 mJ/cm(2)/session, twice a week for 17 weeks), led to 50% reduction in multiplicity of skin tumors. In addition, the total tumor burden of squamous cell carcinomas was reduced by 5.5-fold. The identification of new agents for protection against UV radiation-induced skin cancer and understanding of their mechanism(s) of action is especially important in view of the fact that human skin cancers represent a significant source of increasing morbidity and mortality.
Dinkova-Kostova
Albena T
AT
The Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N Wolfe Street, WBSB Room 406, Baltimore, MD 21205, USA.
Jenkins
Stephanie N
SN
Wehage
Scott L
SL
Huso
David L
DL
Benedict
Andrea L
AL
Stephenson
Katherine K
KK
Fahey
Jed W
JW
Liu
Hua
H
Liby
Karen T
KT
Honda
Tadashi
T
Gribble
Gordon W
GW
Sporn
Michael B
MB
Talalay
Paul
P
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D019610:Cytoprotection / Q000187:drug effects; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D051379:Mice; D008812:Mice, Hairless; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000378:metabolism*; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D014315:Triterpenes / Q000008:administration & dosage*; D014466:Ultraviolet Rays / Q000009:adverse effects
D014315:Triterpenes; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase