Carcinogenesis Advance Access originally published online on November 24, 2006
Carcinogenesis 2007 28(5):1008-1020; doi:10.1093/carcin/bgl233
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Biological assays and genomic analysis reveal lipoic acid modulation of endothelial cell behavior and gene expression
Centro di Biotecnologie Avanzate, Genova, Italy
1 Servizio di Oncologia Sperimentale-A Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
2 Dipartimento di Scienze Cliniche e Biologiche, Università dell'Insubria, Varese, Italy
3 Polo Scientifico e Tecnologico, IRCCS Multimedica, Via Fantoli, 16/15, 20100 Milano, Italy
* To whom correspondence should be addressed. Tel: +39 02 55406574; Fax: +39 101 5737231; Email: adriana.albini{at}multimedica.it
Lipoic acid (LA) is a sulfated antioxidant produced physiologically as a coenzyme of the pyruvate dehydrogenase complex; it is currently used for treatment of non-insulin-dependent diabetes to favor the cellular uptake of glucose. We have previously described the angiopreventive potential of molecules sharing common features with LA: N-acetyl cysteine, epigallocatechin-3-gallate and xanthohumol. To expand these studies, we have tested the capacity of LA to modulate angiogenesis in tumor growth using a Kaposi's sarcoma model. Endothelial cells exposed to LA displayed a dose-dependent reduction of cell migration and a time-dependent modulation of the phosphorylation of key signaling molecules. In vivo, LA efficiently repressed angiogenesis in matrigel plugs and KS-Imm tumor growth. We analyzed modulation of gene expression in endothelial cells treated with LA for 5 h (early response), finding a mild anti-apoptotic, antioxidant and anti-inflammatory response. A group of LA-targeted genes was selected to perform real-time polymerase chain reaction time-lapse experiments. The long-term gene regulation (48 h and 4 days) shows higher rates of modulation as compared with the array data, confirming that LA is able to switch the regulation of several genes linked to cell survival, inflammation and oxidative stress. LA induced the production of tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) in KS-Imm and activin-A in KS-Imm and endothelial cells; these factors show anti-angiogenic activity in vivo contributing to explain the inhibitory effect of LA on neovascularization. According to our data, LA has promising anti-angiogenic properties, though its influence on central metabolic pathways should suggest more caution about its widespread and not prescribed use at pharmacological doses.
Abbreviations: EGCG, epigallocatechin-3-gallate; GPCR, G protein-coupled receptor; HO-1, heme oxygenase-1; KS-CM, Kaposi's sarcoma cell-conditioned medium; LA, lipoic acid; NAC, N-acetyl cysteine; NF-kB, nuclear factor-kappaB; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; TBS, Tris-buffered saline; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-alpha-related apoptosis-inducing ligand; VEGF, vascular endothelial growth factor
Received June 9, 2006; revised October 17, 2006; accepted November 17, 2006.
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