SQUALAMINE

Molecular Weight: 627.963 g/mol
Molecular Formula: C₃₄H₆₅N₃O₅S

Source: The shark Squalus acanthus (CHORDATA)
Activity: Anti-tumor agent; Anti-angiogenic agent
Status: Phase I/Phase II clinical trials; also sold as a non FDA-approved dietary supplement

Squalamine is an aminosterol isolated from the stomach and liver of the spiny dogfish, Squalus acanthus, a common New England coastal shark species.

When it was discovered in 1993, the compound was reported to exhibit broad-spectrum antibiotic activity. Squalamine was licensed to Magainin Pharmaceuticals (now Genaera Corporation) for development. It has progressed to Phase II clinical trials as part of a combination treatment for non-responding solid tumors, and as a primary treatment against ovarian cancer. Phase I prostate cancer trials were slated to commence some time in 2004 and there is data suggesting efficacy against the commonest and deadliest brain tumors as well.

Of considerable interest is published evidence suggesting that squalamine exhibits anti-angiogenic activity under certain conditions (angiogenesis is the formation and differentiation of blood vessels). The speculation and hope of researchers is that squalamine starves tumors by preventing the typical proliferation of blood vessels they require for nourishment. If this is the case, a squalamine-derived anti-tumor drug may be particularly useful since its use should not select for drug resistence in treated cancers because the target of the drug is not the tumor itself but rather the blood vessels supplying the tumor.

The exact method of action is being investigated, but squalamine appears similar to another shark-derived product, neovastat, in its ability to inhibit tumor production of Vascular Endothelial Growth Factor (VEGF) and other such growth factor signals. Additionally, squalamine appears capable of inducing endothelial cell inactivation and apoptosis through inhibition of integrin (specialized receptor protein) expression and the disruption of cytoskeletal formation. Because squalamine is not a protein it can be taken orally as a pill, unlike other anti-angiogenic drugs being evaluated which must be administered intravenously to ensure they are not destroyed by digestive enzymes.

In addition to squalamine's potential as an anti-tumor drug, the compound's licensee Genaera Corporation has also reported very promising Phase I and Phase II clinical results when the drug is used for the treatment of vision problems relating to age-related macular degeneration. In these cases, he drug's anti-angiogenic activity appears to inhibit the choroidal neovascularization associated with this eye condition.

NCBI PubChem compound summary page - [ LINK ]

NCBI PubMed biomedical literature citations and abstracts - [ LINK ]

References

Newman DJ, and GM Cragg. 2004. Advanced preclinical and clinical trials of natural products and related compounds from marine sources. Current Medicinal Chemistry 11:1693-1713.

Press Release: Genaera reports squalamine improves vision in age-related macular degeneration
http://www.genaera.com/pressreleases/2003_aug4.html