Ojo-Amaize Emmanuel A, Nchekwube Emeka J, Cottam Howard B, Bai Ruoli, Verdier-Pinard Pascal, Kakkanaiah Vellalore N, Varner Judith A, Leoni Lorenzo, Okogun Joseph I, Adesomoju Akinbo A, Oyemade Olusola A, Hamel Ernest
Immune Modulation, Inc. and Paraquest, Inc., Bloomington, California 92316, USA.
Cancer Res. 2002 Jul 15;62(14):4007-14.
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.
我们之前已经表明，低雌激素（HE），一种天然二萜类化合物[双环(9,3,1)十五烷]，是一种有效的非甾体抗炎药。在本报告中，我们证明HE在体外也能抑制多种人和小鼠肿瘤细胞系的生长，浓度范围为0.3至10微摩尔，并且在艾姆斯试验中作为诱变剂无活性。HE分别对C57BL/6小鼠的B16黑色素瘤生长和C57BL/6×DBA/2 F(1)小鼠的P388D1白血病表现出高效（0.3 - 10毫克/千克剂量范围）的活性。在5毫克/千克的低最大有效剂量下，HE诱导了显著的体内抗肿瘤活性，优于或与大多数测试的标准化疗抗血管生成药物相当：醋酸可的松、长春新碱、博来霉素、阿霉素、5-氟尿嘧啶、环磷酰胺和依托泊苷。除长春新碱外，所有这些药物的最大有效剂量都比HE高得多。HE使人类伯基特淋巴瘤CA46细胞和HeLa（宫颈上皮样癌）细胞的细胞周期停滞在G2 - M期，这是由直接或间接干扰肌动蛋白组装引起的。因此，细胞周期停滞发生在胞质分裂期，这通过双核细胞数量的增加得以证明。此外，HE在体外抑制血管内皮生长因子诱导的细胞增殖，IC(50)为28.6微摩尔，并且它在鸡胚绒毛尿囊膜上显著抑制碱性成纤维细胞生长因子诱导的血管生成，IC50为10微摩尔。此外，HE抑制内皮细胞在玻连蛋白、胶原蛋白和纤连蛋白上的迁移。除了作为非甾体抗炎药的活性外，HE在癌症化疗方面也有前景。
