Metabolic approach to the enhancement of antitumor effect of chemotherapy: a key role of acetyl-L-carnitine.

Abstract

PURPOSE:

Acetyl-L-carnitine (ALC) plays a relevant role in energy metabolism and stress response because of its function in the complex metabolic system regulating the acetyl-CoA levels that provide a source of acetyl groups for metabolic and acetylation-regulated processes. Because acetylation may influence p53 activity/stability and, therefore, the response to platinum compounds, this study was designed to investigate the effect of ALC in combination with platinum compounds.

EXPERIMENTAL DESIGN:

The antiproliferative and antitumor activity studies were done in a panel of human tumor cell lines with functional or defective p53. The antimetastatic drug efficacy was investigated in the s.c. growing H460/M tumor subline, which is able to generate lung metastases.

RESULTS:

ALC enhanced the sensitivity to cisplatin of tumor cells with functional p53. The sensitization by ALC was reflected in an improved in vivo antitumor efficacy of the combination over cisplatin alone in wild-type p53 lung tumors. ALC did not increase the cisplatin efficacy in the p53-mutant SW620 tumor. ALC exhibited a significant antimetastatic activity, and this effect was better exploited in combination with the histone deacetylase inhibitor, ST3595. The in vivo ALC/cisplatin combination caused the activation of p53, associated with protein acetylation and induction of target genes.

CONCLUSIONS:

ALC was effective in enhancing the antitumor potential of platinum compounds in wild-type p53 tumors. ALC, alone and in combination with a histone deacetylase inhibitor, exhibited an outstanding antimetastatic activity. Both effects, likely mediated by protein acetylation, may have implications for platinum-based therapy and combinations with histone deacetylase inhibitors.

• Authors: Claudio Pisano, Loredana Vesci, Ferdinando Maria Milazzo, Mario Berardino Guglielmi, Rosanna Foderà, Marcella Barbarino, Maurizio D'Incalci, Massimo Zucchetti, Giovanna Petrangolini, Monica Tortoreto, Paola Perego, Valentina Zuco, Augusto Orlandi, Daniela Passeri, Paolo Carminati, Claudio Cavazza, Franco Zunino
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 15 Pg. 3944-53 (Aug 01 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20562210 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2010 AACR.

Chemical References

• Histone Deacetylase Inhibitors
• Tumor Suppressor Protein p53
• Acetylcarnitine
• Carboplatin
• Cisplatin

Topics

• Acetylcarnitine (pharmacology)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Carboplatin (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Cisplatin (administration & dosage)
• Female
• Histone Deacetylase Inhibitors (administration & dosage)
• Humans
• In Situ Nick-End Labeling
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Male
• Mice
• Mice, Nude
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays