Differential effects of lovastatin on cisplatin responses in normal human mesothelial cells versus cancer cells: implication for therapy.

Détails

ID Serval
serval:BIB_DC89AC7C7A54
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Differential effects of lovastatin on cisplatin responses in normal human mesothelial cells versus cancer cells: implication for therapy.
Périodique
PLoS One
Auteur(s)
Shi Y., Felley-Bosco E., Marti T.M., Stahel R.A.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Statut éditorial
Publié
Date de publication
2012
Peer-reviewed
Oui
Volume
7
Numéro
9
Pages
e45354
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Résumé
The cancer killing efficacy of standard chemotherapeutic agents such as cisplatin (CDDP) is limited by their side effects to normal tissues. Therefore, research efforts optimizing the safety and efficacy of those agents are clinically relevant. We did screen for agents that specifically protect normal human mesothelial cells against CDDP without reducing the cancer cell killing efficacy. Lovastatin was identified from the screen. Lovastatin at a pharmacologically relevant concentration strongly arrested the proliferation of normal cells, whereas cancer cells were less affected. CDDP-induced DNA damage response was not activated and normal cells showed enhanced tolerance to CDDP when normal cells were treated with the combination of CDDP and lovastatin. We demonstrate that interfering with protein geranylgeranylation is involved in the lovastatin-mediated CDDP protective effect in normal cells. In contrast to normal cells, in cancer cells lovastatin did not change the CDDP-induced response, and cancer cells were not protected by lovastatin. Furthermore, lovastatin at the pharmacological relevant concentration per se induced DNA damage, oxidative stress and autophagy in cancer cells but not in normal mesothelial cells. Therefore, our data suggest that lovastatin has a potential to improve the therapeutic index of cisplatin-based therapy.
Mots-clé
Cell Cycle/drug effects, Cell Proliferation/drug effects, Cells, Cultured, Cisplatin/pharmacology, DNA Damage/drug effects, Epithelium/drug effects, Epithelium/pathology, Humans, Lovastatin/pharmacology, Protein Prenylation/drug effects, Tumor Cells, Cultured
Pubmed
Web of science
Open Access
Oui
Création de la notice
03/08/2014 13:33
Dernière modification de la notice
20/08/2019 16:01
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