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


METHODS
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.
Pisano
Claudio
C
Oncology Area Research & Development, Sigma-Tau, Pomezia, Italy. claudio.pisano@sigma-tau.it
Vesci
Loredana
L
Milazzo
Ferdinando Maria
FM
Guglielmi
Mario Berardino
MB
Foderà
Rosanna
R
Barbarino
Marcella
M
D'Incalci
Maurizio
M
Zucchetti
Massimo
M
Petrangolini
Giovanna
G
Tortoreto
Monica
M
Perego
Paola
P
Zuco
Valentina
V
Orlandi
Augusto
A
Passeri
Daniela
D
Carminati
Paolo
P
Cavazza
Claudio
C
Zunino
Franco
F
D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D056572:Histone Deacetylase Inhibitors; D016159:Tumor Suppressor Protein p53; D000108:Acetylcarnitine; D016190:Carboplatin; D002945:Cisplatin