and cisplatin block angiogenesis and growth of human ovarian cancer cells with
or without HER-2 gene overexpression
Li D, Williams JI, Pietras RJ
School of Medicine, Department of Medicine, Division of Hematology-Oncology and
Jonsson Comprehensive Cancer Center, Los Angeles, California, CA 90095, USA
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
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.
11973639 [PubMed - indexed for MEDLINE]