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Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression

Abstract

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.

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Acknowledgements

We dedicate this article to the memory of Dr James A Roberts (1947–2001), Professor of Gynecologic Oncology at Stanford University, a friend and a leader in ovarian cancer research who provided many helpful discussions. We also thank Dr Kenneth Holroyd, Dr Dennis J Slamon, Dr Mark Pegram and Dr Rebecca Rausch for advice in the execution of this work. This work was supported by grants from the National Institutes of Health (R29CA60835), the United States Department of Defense Ovarian Cancer Research Program (OC990068), and the Stiles Program in Integrative Oncology.

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Correspondence to Richard J Pietras.

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Li, D., Williams, J. & Pietras, R. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression. Oncogene 21, 2805–2814 (2002). https://doi.org/10.1038/sj.onc.1205410

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Keywords

  • VEGF
  • erb B2/neu
  • MAP kinase
  • carboplatin
  • vascular endothelial cells

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