Resveratrol Enhances Etoposide‐Induced Cytotoxicity through Down‐Regulating ERK 1/2 and AKT ‐Mediated X‐ray Repair Cross‐Complement Group 1 ( XRCC 1) Protein Expression in Human Non‐Small‐Cell Lung Cancer Cells

Etoposide ( VP ‐16), a topoisomerase II inhibitor, is an effective anti‐cancer drug used for the treatment of non‐small‐cell lung cancer ( NSCLC ). Resveratrol is a naturally occurring polyphenolic compound that has been proved to have anti‐cancer activity. XRCC 1 is an important scaffold protein involved in base excision repair that is regulated by ERK 1/2 and AKT signals and plays an important role in the development of lung cancer. However, the role of ERK 1/2 and AKT ‐mediated XRCC 1 expression in etoposide treatment alone or combined with resveratrol‐induced cytotoxicity in NSCLC cells has not been identified. In this study, etoposide treatment increased XRCC 1 mRNA and protein expression through AKT and ERK 1/2 activation in two NSCLC cells, H1703 and H1975. Knockdown of XRCC 1 in NSCLC cells by transfection of XRCC 1 si RNA or inactivation of ERK 1/2 and AKT resulted in enhancing cytotoxicity and cell growth inhibition induced by etoposide. Resveratrol inhibited the expression of XRCC 1 and enhanced the etoposide‐induced cell death and anti‐proliferation effect in NSCLC cells. Furthermore, transfection with constitutive active MKK 1 or AKT vectors could rescue the XRCC 1 protein level and also the cell survival suppressed by co‐treatment with etoposide and resveratrol. These findings suggested that down‐regulation of XRCC 1 expression by resveratrol can enhance the chemosensitivity of etoposide in NSCLC cells.