Angioprevention: Targeting angiogenesis and inflammation in prevention strategies

ED03-03

Angiogenesis is necessary for solid tumor growth and dissemination, a promising target not only in cancer therapy but also in prevention. The principle of cancer chemoprevention is based on the use of agents that, while devoid of collateral effects, are able to interfere with processes associated with malignant progression. In working with many chemoprevention agents, we recently observed that angiogenesis is a common and key target of most chemopreventive molecules. We termed "angioprevention" the concept that effective chemoprevention targets angiogenesis (1). The cancer microenvironment encompasses a series of complex interactions and communications between tumor cells and host cells, in particular endothelial and inflammatory cells, that promote progression to malignancy. We sought to identify molecules and pathways to prevent tumor development by targeting the microenvironment (2) and inflammatory angiogenesis (3).
 We have shown that various molecules, including flavonoids, antioxidants and retinoids, act in the tumor micro-environment and inhibit the recruitment and/or activation of endothelial cells. We have shown that N-acetyl-cysteine (NAC), the green tea flavonoid epigallocatechin-3-gallate (EGCG) and the chalcone Xanthohumol (XN), and the Akt inhibitor deguelin all prevent angiogenesis in the Matrigel sponge angiogenic assay in vivo and inhibit the growth of the highly angiogenic Kaposi's sarcoma tumor cells (KS-Imm) in nude mice. The synthetic retinoid 4-hydroxyfenretinide (4HPR) also shows similar anti-angiogenic and anti-tumor effects.
 To examine the molecular mechanisms involved in their activity, we have performed microarray expression profiling of endothelial cells in response to angiopreventive molecules using the Affymetrix GeneChipTM platform (4). NAC and EGCG showed similar effects no drastic changes in gene expression were observed, with consistent with the absence of toxicity. Many of the genes that respond to both drugs are involved in angiogenesis-related processes and give direct clues to the observed angiopreventive activity, in particular, we find repression of the NF-kB pathway. Inhibition of the Akt and NF-kB pathways are a consistent finding for most angioprevention molecules, including NAC, EGCG, XN and deguelin. The synthetic retinoid 4HPR followed a quite different pathway of regulation linked to the expression of anti-angiogenic molecules in the TGF-beta pathway, MIC1 and BMP2 (5).
 We have now shown that the triterpenoid CDDO-Methylesther is a remarkably potent inhibitor of angiogenesis and angiogenic tumor growth, effective at doses as low as 0.003 mg/kg body weight. The triterpenoids have also been shown to inhibit the NF-kB pathway, consistent with the concept that endothelial NF-kB is central to angiogenesis.
 The key and common mechanism of targeting NF-kB by these agents suggest that he same group of molecules will show anti-inflammatory properties. We have shown that EGCG is a potent anti-inflammatory agent in vivo (6), and have now found similar properties for another angioprevention agent, Hyperforin (7).
 References:
 (1) Tosetti, F., N. Ferrari, S. De Flora and A. Albini. Angioprevention: angiogenesis is a common and key target for cancer chemopreventive agents. Faseb J. 16: 2-14, 2002.
 (2) Albini A. and Sporn M.B. The tumour microenvironment as a target for chemoprevention. Nature Rev Cancer 2007.
 (3) Albini, A., Tosetti, F., Benelli, R., and Noonan DM. Tumor Inflammatory Angiogenesis and its Chemoprevention. Cancer Res. 65:(23), 2005.
 (4) Pfeffer, U., Ferrari, N., Dell'Eva, R., Indraccolo, S., Morini, M., Noonan, D.M., Albini, A. Molecular Mechanisms of Action of Angiopreventive Anti-Oxidants on Endothelial Cells: Microarray Gene Expression Analyses. Mutat. Res. August 3 2005.
 (5) Ferrari, N., Pfeffer, U., Dell'Eva, R., Ambrosini, C., Noonan, D.M., Albini, A. The TGF-beta family members BMP-2 and MIC-1 as mediators of the anti-angiogenic activity of 4-Hydroxyphenylretinamide. Clin. Cancer Res. 15: 4610-9. 2005.
 (6) Dona, M., I. Dell'Aica, F. Calabrese, R. Benelli, M. Morini, A. Albini and S. Garbisa. Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis. J Immunol. 170: 4335-41, 2003.
 (7) Dell'aica I, Niero R, Piazza F, Cabrelle A, Sartor L, Colalto C, Brunetta E, Lorusso G, Benelli R, Albini A, Calabrese F, Agostini C, Garbisa S. Hyperforin blocks neutrophil activation of MMP-9, motility and recruitment,and restrains inflammation-triggered angiogenesis and lung fibrosis. Journal of Pharmacology and Experimental Therapeutics May;321(2):492-500, 2007.