Li Dan, Williams Jon I, Pietras Richard J
UCLA School of Medicine, Department of Medicine, Division of Hematology-Oncology and Jonsson Comprehensive Cancer Center, Los Angeles, California, CA 90095, USA.
Oncogene. 2002 Apr 25;21(18):2805-14. doi: 10.1038/sj.onc.1205410.
Angiogenesis is important for growth and progression of ovarian cancers. Squalamine is a natural antiangiogenic sterol, and its potential role in treatment of ovarian cancers with or without standard cisplatin chemotherapy was assessed. Since HER-2 gene overexpression is associated with cisplatin resistance in vitro and promotion of tumor angiogenesis in vivo, the response of ovarian cancer cells with or without HER-2 gene overexpression to squalamine and cisplatin was evaluated both in tumor xenograft models and in tissue culture. Ovarian cancer cells with or without HER-2 overexpression were grown as subcutaneous xenografts in nude mice. Animals were treated by intraperitoneal injection with control vehicle, cisplatin, squalamine or cisplatin combined with squalamine. At the end of the experiment, tumors were assessed for tumor growth inhibition and for changes in microvessel density and apoptosis. Additional in vitro studies evaluated effects of squalamine on tumor and endothelial cell growth and on signaling pathways in human endothelial cells. Profound growth inhibition was elicited by squalamine alone and by combined treatment with squalamine and cisplatin for both parental and HER-2-overexpressing ovarian tumor xenografts. Immunohistochemical evaluation of tumors revealed decreased microvessel density and increased apoptosis. Although HER-2-overexpressing tumors had more angiogenic and less apoptotic activity than parental cancers, growth of both tumor types was similarly suppressed by treatment with squalamine combined with cisplatin. In in vitro studies, we found that squalamine does not directly affect proliferation of ovarian cells. However, squalamine significantly blocked VEGF-induced activation of MAP kinase and cell proliferation in human vascular endothelial cells. The results suggest that squalamine is anti-angiogenic for ovarian cancer xenografts and appears to enhance cytotoxic effects of cisplatin chemotherapy independent of HER-2 tumor status.
血管生成对卵巢癌的生长和进展至关重要。角鲨胺是一种天然的抗血管生成固醇，评估了其在卵巢癌治疗中（无论是否联合标准顺铂化疗）的潜在作用。由于HER-2基因过表达在体外与顺铂耐药相关，在体内促进肿瘤血管生成，因此在肿瘤异种移植模型和组织培养中评估了有无HER-2基因过表达的卵巢癌细胞对角鲨胺和顺铂的反应。有无HER-2过表达的卵巢癌细胞在裸鼠体内作为皮下异种移植物生长。动物通过腹腔注射对照载体、顺铂、角鲨胺或顺铂联合角鲨胺进行治疗。实验结束时，评估肿瘤的生长抑制情况以及微血管密度和细胞凋亡的变化。额外的体外研究评估了角鲨胺对肿瘤和内皮细胞生长以及人内皮细胞信号通路的影响。单独使用角鲨胺以及角鲨胺和顺铂联合治疗对亲本型和HER-2过表达的卵巢肿瘤异种移植物均产生了显著的生长抑制作用。对肿瘤的免疫组织化学评估显示微血管密度降低，细胞凋亡增加。尽管HER-2过表达的肿瘤比亲本型癌症具有更多的血管生成活性和更少的细胞凋亡活性，但两种肿瘤类型的生长均被角鲨胺联合顺铂治疗同样地抑制。在体外研究中，我们发现角鲨胺不会直接影响卵巢细胞的增殖。然而，角鲨胺显著阻断了VEGF诱导的人血管内皮细胞中MAP激酶的激活和细胞增殖。结果表明，角鲨胺对卵巢癌异种移植物具有抗血管生成作用，并且似乎增强了顺铂化疗的细胞毒性作用，而与HER-2肿瘤状态无关。
