Paclitaxel and Cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine.
OBJECTIVE
Antineoplastic drugs belonging to platinum or taxane families are severely neurotoxic, inducing the onset of disabling peripheral neuropathies with different clinical signs. Acetyl-L-carnitine (ALC) is a natural occurring compound with a neuroprotective activity in several experimental paradigms. In this study we have tested the hypothesis that ALC may have a protective role on cisplatin and paclitaxel-induced neuropathy.


METHODS
Sensory nerve conduction velocity (SNCV) was measured in rats before, at end, and after an additional follow-up period from treatments with cisplatin, paclitaxel, or with the respective combination with ALC. In addition, serum from treated animals was collected to measure the levels of circulating NGF, and left sciatic nerves were processed for light and electron microscope observations. ALC interference on cisplatin and paclitaxel antitumor activity and protective mechanisms were investigated using several in vitro and in vivo models.


RESULTS
ALC cotreatment was able to significantly reduce the neurotoxicity of both cisplatin and paclitaxel in rat models, and this effect was correlated with a modulation of the plasma levels of NGF in the cisplatin-treated animals. Moreover, experiments in different tumor systems indicated the lack of interference of ALC in the antitumor effects of cisplatin and paclitaxel. The transcriptional profile of gene expression in PC12 cells indicated that ALC, in the presence of NGF, was able to positively modulate NGFI-A expression, a gene relevant in the rescue from tissue-specific toxicity. Finally, the transcriptionally ALC-mediated effects were correlated to increase histone acetylation.


CONCLUSIONS
In conclusion, our results indicate that ALC is a specific protective agent for chemotherapy-induced neuropathy after cisplatin or paclitaxel treatment without showing any interference with the antitumor activity of the drugs.
Pisano
Claudio
C
Research and Development, Sigma-Tau S.p.A. Industrie Farmaceutiche Riunite, Rome, Italy. claudio.pisano@sigmatau.it
Pratesi
Graziella
G
Laccabue
Diletta
D
Zunino
Franco
F
Lo Giudice
Pietro
P
Bellucci
Augusta
A
Pacifici
Licia
L
Camerini
Barbara
B
Vesci
Loredana
L
Castorina
Massimo
M
Cicuzza
Sandra
S
Tredici
Giovanni
G
Marmiroli
Paola
P
Nicolini
Gabriella
G
Galbiati
Stefania
S
Calvani
Menotti
M
Carminati
Paolo
P
Cavaletti
Guido
G
D000108:Acetylcarnitine / Q000502:physiology*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000188:drug therapy; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D023421:Models, Animal; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar
D009498:Neurotoxins; D000108:Acetylcarnitine; D017239:Paclitaxel; D002945:Cisplatin