Pemetrexed downregulates ERCC1 expression and enhances cytotoxicity effected by resveratrol in human nonsmall cell lung cancer cells
Journal
Naunyn-Schmiedeberg's Archives of Pharmacology
Journal Volume
386
Journal Issue
12
Pages
1047-1059
Date Issued
2013
Author(s)
Chen R.-S.
Chiu H.-C.
Wo T.-Y.
Huang Y.-J.
Tseng S.-C.
Chen H.-J.
Huang Y.-C.
Jian Y.-J.
Lee W.-T.
Lin Y.-W.
Abstract
The multitargeted antifolate pemetrexed has demonstrated certain clinical activities against nonsmall cell lung cancer (NSCLC). Resveratrol (3,5,4-trihydroxy-trans-stilbene) is a polyphenol found in grapes and other plants and has great potential as a preventative and therapeutic agent due to its anticarcinogenic activity. The efficacy of adding resveratrol to pemetrexed to prolong the survival of patients with NSCLC still remains unclear. The excision repair cross-complementation 1 (ERCC1) is a DNA repair gene coding 5′ endonuclease in nucleotide excision repair and is overexpressed in chemo- or radioresistant carcinomas. In this study, resveratrol (10-50 μM) inhibited cell survival in two NSCLC cells, H520 and H1975. Treatment with resveratrol increased ERCC1 messenger RNA and protein levels in a MKK3/6-p38 MAPK signal activation-dependent manner. Furthermore, blocking p38 MAPK activation by SB202190 or knocking down ERCC1 expression by transfection with small interfering RNA of ERCC1 enhanced the cytotoxicity of resveratrol. Combining resveratrol with pemetrexed resulted in a synergistic cytotoxic effect, accompanied with the reduction of phospho-p38 MAPK and ERCC1 protein levels, and a DNA repair capacity. Expression of constitutively active MKK6 (MKK6E) or HA-p38 MAPK vectors significantly rescued the decreased p38 MAPK activity, and restored ERCC1 protein levels and cell survival in resveratrol and pemetrexed cotreated NSCLC cells. In this study, for the first time, we have demonstrated the synergistic effect of combined treatment with resveratrol and pemetrexed in human NSCLC cells through downregulation of the MKK3/6-p38 MAPK-ERCC1 signal, suggesting a potential benefit of combining resveratrol and pemetrexed to treat lung cancer in the future. ? 2013 Springer-Verlag Berlin Heidelberg.
SDGs
Other Subjects
4 (4 fluorophenyl) 2 (4 hydroxyphenyl) 5 (4 pyridyl)imidazole; cell DNA; cisplatin; excision repair cross complementing protein 1; gemcitabine; messenger RNA; mitogen activated protein kinase 14; mitogen activated protein kinase kinase 3; mitogen activated protein kinase kinase 6; pemetrexed; resveratrol; small interfering RNA; taxane derivative; article; cancer cell; cancer inhibition; cancer survival; cell survival; cell viability; controlled study; DNA repair; down regulation; drug cytotoxicity; drug efficacy; drug potentiation; enzyme activity; human; human cell; lung non small cell cancer; protein expression; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; DNA Repair; DNA-Binding Proteins; Dose-Response Relationship, Drug; Down-Regulation; Endonucleases; Enzyme Activation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glutamates; Guanine; Humans; Lung Neoplasms; MAP Kinase Kinase 3; MAP Kinase Kinase 6; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; RNA Interference; RNA, Messenger; Signal Transduction; Stilbenes; Time Factors; Transfection
Type
journal article