Enhancement of mitomycin C-induced cytotoxicity by curcumin results from down-regulation of MKK1/2-ERK1/2-mediated thymidine phosphorylase expression.
Basic Clin Pharmacol Toxicol
; 110(3): 298-306, 2012 Mar.
Article
en En
| MEDLINE
| ID: mdl-21973306
ABSTRACT
Curcumin (diferuloylmethane), a phenolic compound obtained from the rhizome of Curcuma longa, has been found to inhibit cell proliferation in various human cancer cell lines, including non-small cell lung cancer (NSCLC). Thymidine phosphorylase (TP) is considered an attractive therapeutic target, because increased TP expression can suppress cancer cell death induced by DNA-damaging agents. Mitomycin C (MMC), a chemotherapeutic agent used to treat NSCLC, inhibits tumour growth through DNA cross-linking and breaking. Whether MMC can affect TP expression in NSCLC is unknown. Therefore, in this study, we suggested that curcumin enhances the effects of MMC-mediated cytotoxicity by decreasing TP expression and ERK1/2 activation. Exposure of human NSCLC cell lines H1975 and H1650 to curcumin decreased MMC-elicited phosphorylated MKK1/2-ERK1/2 protein levels. Moreover, curcumin significantly decreased MMC-induced TP protein levels by increasing TP mRNA and protein instability. Enhancement of ERK1/2 activation by constitutively active MKK1/2 (MKK1/2-CA) increased TP protein levels and cell viability in curcumin- and MMC-co-treated cells. In contrast, U0126, a MKK1/2 inhibitor, augmented the cytotoxic effect and the down-regulation of TP by curcumin and MMC. Specific inhibition of TP by siRNA significantly enhanced MMC-induced cell death and cell growth inhibition. Our results suggest that suppression of TP expression or administration of curcumin along with MMC may be a novel lung cancer therapeutic modality in the future.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Mitomicina
/
Carcinoma de Pulmón de Células no Pequeñas
/
Curcumina
/
Neoplasias Pulmonares
Límite:
Humans
Idioma:
En
Revista:
Basic Clin Pharmacol Toxicol
Asunto de la revista:
FARMACOLOGIA
/
TOXICOLOGIA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Taiwán