Etoposide (VP-16), a topoisomerase II inhibitor, is an effective anti-cancer drug used for the treatment of non-smallcell lung cancer (NSCLC). Resveratrol is a naturally occurring polyphenolic compound that has been proved to have anti-cancer activity. XRCC1 is an important scaffold protein involved in base excision repair that is regulated by ERK1/2 and AKT signals and plays an important role in the development of lung cancer. However, the role of ERK1/2 and AKT-mediated XRCC1 expression in etoposide treatment alone or combined with resveratrol-induced cytotoxicity in NSCLC cells has not been identified. In this study, etoposide treatment increased XRCC1 mRNA and protein expression through AKT and ERK1/2 activation in two NSCLC cells, H1703 and H1975. Knockdown of XRCC1 in NSCLC cells by transfection of XRCC1 siRNA or inactivation of ERK1/2 and AKT resulted in enhancing cytotoxicity and cell growth inhibition induced by etoposide. Resveratrol inhibited the expression of XRCC1 and enhanced the etoposide-induced cell death and anti-proliferation effect in NSCLC cells. Furthermore, transfection with constitutive active MKK1 or AKT vectors could rescue the XRCC1 protein level and also the cell survival suppressed by co-treatment with etoposide and resveratrol. These findings suggested that down-regulation of XRCC1 expression by resveratrol can enhance the chemosensitivity of etoposide in NSCLC cells.Lung cancer, the leading cause of cancer death in the world, is classified as non-small-cell lung cancer (NSCLC) and small-cell lung cancer [1]. NSCLC accounts for 85% of lung cancer cases, and despite aggressive radio-and/or chemotherapy, fewer than 20% of patients reach a 5-year survival. This poor treatment outcome is due to the primary or acquired drug resistance of NSCLC cells to present cytotoxic therapeutic agents [2,3].Etoposide is an epipodophyllotoxin employed in the therapy of a wide spectrum of cancers [4][5][6]. In vitro studies have shown that etoposide increases topoisomerase II-mediated DNA breakage primarily by inhibiting the ability of the enzyme to religate cleaved nucleic acid molecules [7]. XRCC1 (X-ray repair cross-complementing group 1) is a key mediator of base excision repair (BER). Deficiency of XRCC1 in mice results in embryonic lethality [8,9]. XRCC1 interacts with enzymatic factors such as polyadenosine diphosphate (ADP)-ribose polymerase, DNA ligase III and DNA polymerase b to facilitate efficient repair of DNA single-strand breaks (SSBs) [10]. Down-regulation of XRCC1 expression in human breast cancer cell lines resulted in decreased SSB repair capacity and hypersensitivity to methyl methane sulphonate (MMS) [11]. A previous study has shown that the PI3K-AKT pathway regulates the basal expression of XRCC1 in non-irradiated cells, and MKK1/2-ERK1/2 is essential for the induction of XRCC1 after exposure to radiation [12]. However, whether ERK1/2 and AKT signals involve in regulating XRCC1 expression upon etoposide treatment and its role in the etoposide-induced cytotoxicity in NSCL...