Angiogenesis New Targets for the Development of Anticancer Chemotherapies

Abstract

Angiogenesis is the process by which new blood vessels are formed from preexisting microvasculature. To ensure an adequate blood supply, tumor cells release angiogenic factors that are capable of promoting nearby blood vessels to extend vascular branches to the tumor. In addition, larger tumors have been shown to release angiogeneic inhibitory factors that prevent blood vessels from sending branches to smaller, more distant tumors that compete for oxygen and nutrients. Angiogenesis is a complex multistep biochemical process, and offers several potential molecular targets for non-cytotoxic anticancer therapies. Strategies for exploiting tumor angiogenesis for novel cancer drug discovery include: (i) inhibition of proteolytic enzymes that breakdown the extracellular matrix surrounding existing capillaries; (ii) inhibition of endothelial cell migration; (iii) inhibition of endothelial cell proliferation; (iv) enhancement of tumor endothelial cell apoptosis. There is also a host of miscellaneous agents that inhibit angiogenesis for which the specific mechanisms are not clear. Several methods have been developed for measuring antiangiogenic activity both in vitro and in vivo. Although there has been intensive research efforts focused at the phenomena of angiogenesis, as well as the search for antiangiogenic agents for more than two decades, many questions remain unanswered with regard to the overall biochemical mechanisms of the angiogenesis process and the potential therapeutic utility of angiogenic inhibitors. Nevertheless potent angiogenic inhibitors capable of blocking tumor growth have been discovered, and appear to have potential for development into novel anticancer therapeutics. However there are still hurdles to be overcome before these inhibitors become mainstream therapies.

Hyperforin, a bio‐active compound of St. John's Wort, is a new inhibitor of angiogenesis targeting several key steps of the process

“…29 Several anti-angiogenic compounds have been shown to inhibit endothelial cell migration invasion. 14,25,[30][31][32][33] Our results show that 10 lM hyperforin produces a remarkable and significant inhibition of the invasive capability of BAE cells and only a slight inhibition of their migratory capability.…”

Disulfiram, a Clinically Used Anti-Alcoholism Drug and Copper-Binding Agent, Induces Apoptotic Cell Death in Breast Cancer Cultures and Xenografts via Inhibition of the Proteasome Activity

“…Many critical enzymes and transcription factors require copper for their activities (1)(2)(3). Angiogenesis, the growth of a tumor blood supply, is essential for tumor growth, invasion, and metastasis (4,5). Tumors without an additional blood supply do not grow larger than 1 to 2 mm 3 (6).…”

“…Tumors without an additional blood supply do not grow larger than 1 to 2 mm 3 (6). Molecular processes of angiogenesis include stimulation of endothelial growth by tumor cytokine production (i.e., vascular endothelial growth factor) and the requirement of copper (but not other trace metals) as an essential cofactor (3)(4)(5)(6). Consistently, high serum or tissue levels of copper were found in many types of human cancers including breast, prostate, colon, lung, and brain (7)(8)(9)(10)(11)(12)(13), although the involved mechanism remains unknown.…”

Sodium diethyldithiocarbamate, an AIDS progression inhibitor and a copper-binding compound, has proteasome-inhibitory and apoptosis-inducing activities in cancer cells

“…Copper is used in a multitude of cellular activities (1,2). It is known that copper is involved in the development of cancers and important for both carcinogenesis and angiogenesis that plays a key role in tumor formation (3,4). Copper appears to act as an essential cofactor for several angiogenic growth factors (5).…”