The inhibition of oncogenic signaling pathways has gained great interest for
cancer therapy. In this context, the
molecular chaperone heat shock protein 90 (HSP90) has emerged as a promising molecular target, since it is critically involved in maintaining stability, integrity and functions of key oncogenic
proteins. A variety of HSP90 inhibitors have been developed in the past decade and have shown convincing anti-neoplastic activity in pre-clinical
tumor models. Importantly, HSP90 inhibitors are predominantly being recognized as "
tumor cell targeting" agents since
cancer cells a) overexpress HSP90
protein, b) highly rely on HSP90 function for maintaining oncogenic signaling, and c) HSP90 inhibitors bind with high affinity to HSP90 in
tumor cells. Nevertheless, results from recent studies also suggest that HSP90 inhibitors elicit anti-angiogenic properties by affecting the PI-3K/Akt/eNOS signal transduction pathway in endothelial cells, as well as through down-regulation of VEGFR-2 expression, a crucial component of the angiogenic process. In addition, blocking HSP90 may also diminish the secretion and expression of
tumor cell-derived pro-angiogenic
growth factors and
cytokines, thus leading to "indirect" anti-angiogenic effects. This review article focuses on the role of HSP90 in angiogenesis and on delineating the effects of HSP90 inhibitors on angiogenic signaling pathways involved in
tumor vascularization.