Carcinogenesis Advance Access published online on November 24, 2006
Carcinogenesis, doi:10.1093/carcin/bgl233
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1 Centro Biotecnologie Avanzate, Genova, ITALY
* To whom correspondence should be addressed. Lipoic acid (LA) is a sulphated antioxidant produced physiologically as a co-enzyme of the pyruvate dehydrogenasis 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 Xanthumol. 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 hours (early response), finding a mild anti-apoptotic, anti-oxidant and anti-inflammatory response. A group of LA-targeted genes was selected to perform Real Time PCR time-lapse experiments. The long term gene regulation (48 hours and 4 days) shows higher rates of modulation as compared to 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 TRAIL in KS-Imm and Activin-A in KS-Imm and endothelial cells, these factors show antiangiogenic activity in vivo contributing to explain the inhibitory effect of LA on neovascularization. According to our data LA has promising antiangiogenic properties, though its influence on central metabolic pathways should suggest more caution about its widespread and not prescribed use at pharmacological doses.
Received June 9, 2006
Revised October 17, 2006
Accepted November 17, 2006
CANCER PREVENTION
Biological assays and genomic analysis reveal lipoic acid modulation of endothelial cell behavior and gene expression
Patrizia Larghero 1, Roberta Venè 2, Simona Minghelli 1, Giorgia Travaini 1, Monica Morini 2, Nicoletta Ferrari 2, Ulrich Pfeffer 2, Douglas Noonan 3, Adriana Albini 4 *, and Roberto Benelli 2
2 Servizio di Oncologia Sperimentale-A Istituto Nazionale per la Ricerca sul Cancro, Genova, ITALY
3 Dipartimento di Scienze Cliniche e Biologiche, Università dell'Insubria, Varese, ITALY
4 Polo Scientifico e Tecnologico, IRCCS Multimedica, Milano, ITALY
Adriana Albini, E-mail: adriana.albini{at}multimedica.it
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