Antiangiogenic Agents: Studies on Fumagillin and Curcumin Analogs

Abstract

Cancer is a general term used to describe many disease states, each of which are characterized by abnormal cell proliferation. The causes which bring about this abnormal cellular behavior are specific to each type of cancer. The success of tumor-targeted therapy is limited by this diversity. One common denominator for all types of cancer is the requirement of a suitable blood supply. Therefore, tumor vasculature has emerged as a potential target for therapeutic intervention. New blood vessel growth from preexisting vasculature stimulated by biochemical signals is termed angiogenesis. Tumor masses require a constant supply of oxygen and nutrients, and a means of efficient waste removal to ensure sustained development. Diffusion from nearby capillaries can supply adequate nutrition for tumors less than 2 mm in size, but for continued growth the tumors must develop their own blood supply. Alteration of the delicate balance of angiogenic stimulating factors and angiogenic inhibitors results in the phenotypic change from quiescence to active endothelial proliferation. To date, this angiogenic switch is not completely understood. The goal of antiangiogenic therapy is to interfere with these mechanisms and prevent tumor cells from developing a viable blood supply. Fumagillin is a naturally occurring antifungal agent. Curcumin is a natural product isolated from the spice turmeric. Both compounds have been shown to have antiangiogenic properties in vitro and in vivo. This paper describes efforts to design and prepare fumagillin and curcumin analogs and evaluate their corresponding antiangiogenic activities.

Wnt pathway antagonists and angiogenesis

“…Curcumin was shown to inhibit cancer (Conney et al, 1991;Huang et al, 1994), and was later reported to function as an angiogenic inhibitor (Arbiser et al, 1998). Since this report, the antiangiogenic effect of curcumin and its potential mechanism of action have been studied extensively in different models and organs (Adams et al, 2004;Furness et al, 2005;Bhandarkar and Arbiser, 2007;Kunnumakkara et al, 2008;Varinska et al, 2010). Several signaling transduction pathways have been found to be regulated by curcumin, including protein kinase C, NF-kappaB and AP-1 (Bhandarkar and Arbiser, 2007).…”

New mechanisms and therapeutic potential of curcumin for colorectal cancer

“…It has been shown that curcumin has direct antiangiogenic activity in vitro [205,206] and in vivo [206 -208], which may explain its chemopreventive effect at the level of tumour growth and metastasis. Possible antiangiogenic mechanisms are been postulated like the down regulation of proangiogenic genes such as VEGF and angiopoitin and a decrease in migration and invasion of endothelial cells [101].…”

Metabolism and Anticancer Activity of the Curcumin Analogue, Dimethoxycurcumin

“…18, 19 and reviewed in refs. 3,20,21). In this context, curcumin induces apoptosis by a redox-dependent mechanism (18); reduction in the nuclear expression of nuclear factor-nB (19); inhibition of telomerase activity (22); down-regulation of Notch-1 signaling (23); and cytochrome c release, Bid cleavage and caspase-9 and caspase-3 activation, and down-regulation of the antiapoptotic proteins Bcl-2, Bcl-X L , and Myc (20,24).…”