PT - JOURNAL ARTICLE AU - Yun-Wei Lin AU - Min-Shao Tsai AU - Shao-Hsing Weng AU - Ya-Hsun Kuo AU - Yu-Fan Chiu TI - Synergistic effect of curcumin and cisplatin via downregulation of thymidine phosphorylase and ERCC1 AID - 10.1124/mol.111.071316 DP - 2011 Jan 01 TA - Molecular Pharmacology PG - mol.111.071316 4099 - http://molpharm.aspetjournals.org/content/early/2011/04/14/mol.111.071316.short 4100 - http://molpharm.aspetjournals.org/content/early/2011/04/14/mol.111.071316.full AB - Curcumin (diferuloylmethane), a phenolic compound obtained from the rhizome of Curcuma longa, is known to have antiproliferative and antitumor properties. Thymidine phosphorylase (TP), an enzyme of the pyrimidine salvage pathway, is considered an attractive therapeutic target and its expression could suppress cancer cell death induced by DNA damage agents. Excision repair cross-complementary 1 (ERCC1) is a protein involved the process of nucleotide excision repair. The ERCC1 gene is expressed at high levels in cancers and has been associated with resistance to platinum-based chemotherapy. In this study, the effects of curcumin on TP and ERCC1 expression induced by cisplatin in non-small cell lung cancer (NSCLC) cell lines was investigated. Exposure of the NSCLC cells to various concentrations of curcumin (5−40 μM) downregulates the mRNA and protein levels of TP and ERCC1 through destabilization of the mRNA and proteins via a mechanism involving inactivation of MKK1/2-ERK1/2. Depletion of endogenous TP or ERCC1 expression by transfection with specific small interfering RNAs significantly decreases cell viability in curcumin-exposed NSCLC cells. Curcumin enhances the sensitivity of cisplatin treatment for NSCLC through inactivation of ERK1/2 and by decreasing the TP and ERCC1 protein levels. Enhancement of ERK1/2 signaling by constitutively active MKK1/2 (MKK1/2-CA) causes an increase in TP and ERCC1 protein levels and promotes cell viability after cotreatment with curcumin and cisplatin. Enhancement of the cytotoxicity to cisplatin by administration of curcumin is mediated by downregulation of the expression levels of TP and ERCC1 and by inactivation of ERK1/2.