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Hypoestoxide, a Natural Nonmutagenic Diterpenoid with Antiangiogenic and Antitumor Activity

Possible Mechanisms of Action

Immune Modulation, Inc. and Paraquest, Inc., Bloomington, California 92316 [E. A. O-A., E. J. N., H. B. C., V. N. K., J. I. O., O. A. O.]; Screening Technologies Branch, DTP/DCTD, National Cancer Institute, NIH, Frederick, Maryland 21702 [R. B., P. V-P., E. H.]; Cancer Center and Department of Medicine, University of California, San Diego, La Jolla, California 92093 [J. A. V., L. L.]; and Department of Chemistry, University of Ibadan, Nigeria, Africa [A. A. A.]

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 µM 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 F₁ 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 IC₅₀ of 28.6 µM, and it significantly inhibited basic fibroblast growth factor-induced angiogenesis on the chick chorioallantoic membrane, with an IC₅₀ of 10 µM. 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.

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