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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...

Cisplatin is a well-studied and widely used chemotherapeutic agent and is effective in the treatment of the advanced human non-small cell lung cancer (NSCLC). Curcumin is a yellow pigment derived from the rhizome of Curcuma longa and has been proved to have antioxidant and antitumor properties. XRCC1 is an important scaffold protein involved in base excision repair and plays an important role in the development of lung cancer. In this study, we characterize the role of curcumin in the cytotoxicity, p38 MAPK activation, and XRCC1 expression affected by cisplatin in NSCLC cells. We show that curcumin enhanced the cytotoxicity induced by cisplatin in two NSCLC cells, A549 and H1703. Treatment with cisplatin alone increased XRCC1 mRNA and protein expression through p38 MAPK activation. Moreover, SB2023580 (p38 inhibitor) decreased the XRCC1 mRNA and protein stability upon cisplatin treatment. Knockdown of XRCC1 in NSCLC cells by transfection of XRCC1 siRNA or inactivation of p38 MAPK resulted in enhancing the cytotoxicity and cell growth inhibition induced by cisplatin. Curcumin inhibited the expression of XRCC1 in cisplatin-exposed NSCLC cells. Furthermore, transfection with constitutive active MKK6 or HA-p38 MAPK vectors rescued the XRCC1 protein level and also the cell survival suppressed by cisplatin and curcumin combination in A549 and H1703 cells. These findings suggested that the downregulation of XRCC1 expression by curcumin can enhance the chemosensitivity of cisplatin in NSCLC cells.

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