Squalamine is a cholestane steroid conjugated to a spermidine at position C-3. However, it does not have glucocorticoid and mineralocorticoid effects ⁽⁸⁾. Squalamine binds to cell membranes and inhibits the specific membrane Na⁺/H⁺ exchanger NHE3, causing intracellular pH alterations and disruption of intracellular signaling induced by angiogenic growth factors ⁽⁸⁾.

Squalamine alters shape and volume of endothelial cells in embryonic vascular beds, causing narrowing of the vessel lumen and occluding blood flow ⁽¹⁰⁾. These actions inhibit multiple key steps in angiogenesis, including mitogen-induced actin polymerization, cell-cell adhesion, and cell migration, ultimately inhibiting endothelial cell proliferation. Squalamine blocks downstream VEGF signaling pathways, including phosphorylation of p44/p42 MAP kinase in vascular endothelial cells ⁽¹¹⁾. It also disrupts F-actin fibers and induces internalization of vascular endothelial-cadherin from the membrane into the intracellular compartment ⁽¹²⁾. It may also decrease retinal neovascularization that is thought to encourage macular degeneration ⁽¹⁷⁾.

Squalamine is an amphipathic compound that interacts with various membrane glycerophospholipids ⁽⁴⁾. It has a faster killing rate of gram-positive versus -negative bacteria ^{(3) (13) (14)}. It also enhances chemotherapy drug cytotoxicity by promoting tumor cell apoptosis and reducing angiogenesis ^{(10) (15) (16)}. Inhibition of growth factor-induced endothelial cell proliferation and migration contribute to antiangiogenic effects ⁽⁹⁾.