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.