Squalamines in Blockade of Tumor-Associated Angiogenesis and Cancer Progression

SIMPLE SUMMARY: Despite the many ongoing advances in cancer prevention, diagnosis and clinical management, global mortality from human cancers remains at high levels. Notably, more effective treatment of many cancers is advancing due to introduction of novel biologic therapies targeted to tumor signaling and immunologic pathways. Tumor growth is dependent on a sustained blood supply of nutrients and oxygen, and this process termed tumor-associated angiogenesis (TAA) has prognostic and therapeutic importance in several human malignancies. This review addresses use of squalamines to stop tumor growth. This naturally occurring compound can inhibit angiogenesis in tumors thereby reducing malignant progression in preclinical studies and in early clinical trials. ABSTRACT: Mechanisms of action of squalamine in human vascular endothelial cells indicate that this compound attaches to cell membranes, potentially interacting with calmodulin, Na(+)/H(+) exchanger isoform NHE3 and other signaling pathways involved in the angiogenic process. Thus, squalamine elicits blockade of VEGF-induced endothelial tube-like formation in vitro. Further, squalamine reduces growth of several preclinical models of human cancers in vivo and acts to stop metastatic tumor spread, actions due largely to blockade of angiogenesis induced by the tumor and tumor microenvironment. Squalamine in Phase I/II trials, alone or combined with standard care, shows promising antitumor activity with limited side-effects in patients with advanced solid cancers. Increased attention on squalamine regulation of signaling pathways with or without combination treatments in solid malignancies deserves further study.