New nortriterpenoid isolated from anti-rheumatoid arthritic plant, Tripterygium wilfordii, modulates tumor growth and neovascularization.
Preparations of Tripterygium wilfordii, "Thunder God vine", have been used in China to treat rheumatoid arthritis. Rheumatoid arthritis, as well as solid tumors, is closely associated with neovascularization. Antiarthritic drugs therefore may modulate tumor growth as well as neovascularization. We found that a compound purified from T. wilfordii, the nortriterpenoid, demethylzeylasteral (TZ-93), inhibited the proliferation of vascular endothelial cells approximately 30 times more effectively than it did for the proliferation of human tumor cells. In in vitro assays using bovine aortic endothelial cells, TZ-93 at non-toxic doses inhibited cell migration, expression of urokinase-type plasminogen activator (uPA) mRNA and uPA activity. Exogenous addition of uPA restored the inhibitory effect of TZ-93 on cell migration. In dorsal air-sac assays in BALB/c mice, the oral administration of 3 mg/kg/day TZ-93 for 5 days partially inhibited, and 30 mg/kg/day almost completely abrogated, the development of capillary networks induced by human hepatoblastoma cells. Similarly, 0.3 mg/kg/day TZ-93 partially inhibited, and 3 or 30 mg/kg/day almost completely blocked, the growth of mouse B16-F10 melanoma cells in a tumor implantation assay. The highest dose of TZ-93 significantly reduced the growth of well-vascularized tumors with volumes of more than 500 mm3. TZ-93 treatment of tumor-bearing mice significantly decreased the density of microvessels in the tumors. We conclude that TZ-93 may be useful in treating highly vascularized and metastatic tumors as well as other angiogenic diseases.
Ushiro
S
S
Department of Biochemistry, Kyushu University School of Medicine, Maidashi, Fukuoka, Japan.
Ono
M
M
Nakayama
J
J
Fujiwara
T
T
Komatsu
Y
Y
Sugimachi
K
K
Kuwano
M
M
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004790:Enzyme Induction; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010936:Plant Extracts / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry*; D014315:Triterpenes / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis
D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D010936:Plant Extracts; D014315:Triterpenes; C099855:demethylzeylasteral; D014568:Urokinase-Type Plasminogen Activator