Abstract
Abstract Several lines of evidence support that acetyl-L-carnitine (ALC) plays a relevant role as modulator of cellular stress response and may have a protective action in chemotherapy-induced neurotoxicity. ALC is implicated in the regulation of acetyl-CoA levels, a function mediated by carnitine acetyltransferase, thus providing a source of acetyl groups for histone acetylation. Since HDAC inhibitors may influence cellular response to cytotoxic drugs, including DNA damaging agents, it is conceivable that ALC may have a cooperative effect in combination with agents able to modulate protein acetylation. In particular, since the acetylation of wild-type p53, a substrate of HDAC, may influence its activity and stability and, therefore, the response to platinum compounds, this study was designed to investigate the effect of ALC in combination with cisplatin and carboplatin. ALC (100 mg/kg;qdx14, p.o.), in combination with cisplatin (5 mg/kg, i.p., q4dx5), was able to enhance the life-span of mice bearing the EL-4 lymphoma tumor (ILS: ALC plus cisplatin >500%; cisplatin 105% vs control), resulting in 5/7 mice without evidence of disease. In addition, the combination of ALC plus cisplatin significantly increased the antitumor activity of cisplatin in three xenograft models of human non-small cell lung carcinoma (NCI-H460, A549 and NCI-H1650). Noteworthy, in a metastatic NCI-H460 model, an impressive reduction of lung metastasis in ALC and ALC+cisplatin groups was observed as compared with untreated mice. An increased antitumor activity was also observed in the combination of ALC with carboplatin. In addition, ALC produced an enhancement of antitumor activity of a novel HDAC inhibitor. To assess the relevance of acetyl moiety of ALC in the antitumor response, we investigated the activity of the combination of cisplatin with the related compound L-carnitine in NCI-H460 tumor model. In this experiment, L-carnitine did not showed any significative increases of antitumor effect when combined with cisplatin (TVI: 80% cisplatin vs 70% cisplatin plus carnitine), thus confirming a specific effect of ALC. In order to investigate the molecular mechanisms of the ALC-cisplatin interaction, several signal transduction pathways were analysed in H460 tumors by protein analysis and/or gene expression. The results revealed a significant increase of the p53 protein levels (p<0.05 ALC plus cisplatin vs cisplatin), associated Lys373 acetylation, and the up-regulation of genes under control of p53. These observations may have implications for the therapeutic use of ALC in platinum-based chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 566.
Published Version
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