Despite advances in the early detection of
tumors and in the use of
chemotherapy,
radiotherapy and surgery for disease management, the worldwide mortality from human
cancer remains unacceptably high. The treatment of
cancer may benefit from the introduction of novel
therapies derived from natural products. Natural products have served to provide a basis for many of the pharmaceutical agents in current use in
cancer therapy. Emerging research indicates that progressive growth and spread of many solid
tumors depends, in part, on the formation of an adequate blood supply, and this process of
tumor-associated angiogenesis is reported to have prognostic significance in several human
cancers. This review focuses on the potential application in antitumor
therapy of naturally-occurring
steroids that target
tumor-associated angiogenesis.
Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane
steroid conjugated to a
spermidine at position C-3, is known to have strong antiangiogenic activity in vitro, and it significantly disrupts
tumor proliferation and progression in laboratory studies. Work on the interactions of
squalamine with vascular endothelial cells indicate that it binds with cell membranes, inhibits the membrane
Na(+)/H(+) exchanger and may further function as a
calmodulin chaperone. These primary actions appear to promote inhibition of several vital steps in angiogenesis, such as blockade of
mitogen-induced actin polymerization, cell-cell adhesion and cell migration, leading to suppression of endothelial cell proliferation. Preclinical studies with
squalamine have shown additive benefits in
tumor growth delay when
squalamine is combined with
cisplatin,
paclitaxel,
cyclophosphamide,
genistein or
radiation therapy. This compound has also been assessed in early phase clinical trials in
cancer;
squalamine was found to exhibit little systemic toxicity and was generally well tolerated by treated patients with various solid
tumor malignancies, including ovarian, non-small cell lung and breast
cancers. Clinical trials with
squalamine alone or combined with standard
chemotherapies or other
biologic therapies, including
antiangiogenic agents, should be considered for selected
cancer patients, and further study of the mechanism of action and bioactivity of
squalamine is warranted.