Hypoestoxide, a natural nonmutagenic diterpenoid with antiangiogenic and antitumor activity: possible mechanisms of action.
We have shown previously that hypoestoxide (HE), a natural diterpenoid [a bicyclo (9, 3, 1) pentadecane], is a potent nonsteroidal anti-inflammatory drug. In this report, we demonstrate that HE also inhibits the growth of a variety of human and murine tumor cell lines in vitro at concentrations ranging from 0.3 to 10 microM and was inactive as a mutagen in the Ames test. HE exhibited highly potent (0.3-10 mg/kg dose ranges) activities against B16 melanoma growth in C57BL/6 mice and P388D1 leukemia in C57BL/6 x DBA/2 F(1) mice, respectively. At a low maximal effective dose of 5 mg/kg, HE induced significant in vivo antitumor activities that were better than or comparable with most of the standard chemotherapeutic antiangiogenic agents tested: cortisone acetate, vincristine, bleomycin, Adriamycin, 5-fluorouracil, cyclophosphamide, and etoposide. All of the agents, except vincristine, had much higher maximal effective doses than HE. HE arrested the growth of human Burkitt lymphoma CA46 cells and HeLa (cervical epitheloid carcinoma) cells in the G2-M phase of the cell cycle, which was caused by interference, either direct or indirect, with actin assembly. Thus, the cell cycle arrest occurred at cytokinesis, as demonstrated by an increase in the number of binucleate cells. Moreover, HE inhibited vascular endothelial growth factor-induced cell proliferation in vitro, with an IC(50) of 28.6 microM, and it significantly inhibited basic fibroblast growth factor-induced angiogenesis on the chick chorioallantoic membrane, with an IC50 of 10 microM. Furthermore, HE inhibited endothelial cell migration on vitronectin, collagen, and fibronectin. Besides its activity as a nonsteroidal anti-inflammatory drug, HE also has promise for the chemotherapy of cancer.
Ojo-Amaize
Emmanuel A
EA
Immune Modulation, Inc. and Paraquest, Inc., Bloomington, California 92316, USA. Ojoamaize@aol.com
Nchekwube
Emeka J
EJ
Cottam
Howard B
HB
Bai
Ruoli
R
Verdier-Pinard
Pascal
P
Kakkanaiah
Vellalore N
VN
Varner
Judith A
JA
Leoni
Lorenzo
L
Okogun
Joseph I
JI
Adesomoju
Akinbo A
AA
Oyemade
Olusola A
OA
Hamel
Ernest
E
D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D004224:Diterpenes / Q000494:pharmacology* / Q000633:toxicity; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009152:Mutagenicity Tests; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011817:Rabbits; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000199:Actins; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004224:Diterpenes; D006131:Growth Inhibitors; D014404:Tubulin; C432343:hypoestoxide