Curcumin downregulates p38 MAPK-dependent X-ray repair cross-complement group 1 (XRCC1) expression to enhance cisplatin-induced cytotoxicity in human lung cancer cells

Abstract

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.

Synergistic Anticancer Activity of Combined Use of Caffeic Acid with Paclitaxel Enhances Apoptosis of Non-Small-Cell Lung Cancer H1299 Cells in Vivo and in Vitro

“…These findings are consistent with the results of the cell apoptosis assay. Previous studies [31][32][33] suggested that MAPKs can be induced by various compounds and are involved in cell death in NSCLC cells. The MAPK family includes three kinase members including JNK/stress activated protein kinases, P38mapk, and ERK [34].…”

Effect of mitomycin C on X‐ray repair cross complementing group 1 expression and consequent cytotoxicity regulation in human gastric cancer cells

“…Our analysis further revealed that the XRCC1 upregulation was mediated via MAPK phosphorylation. It has been reported that XRCC1 expression is dependent on ERK and p38 activation in non‐small‐cell lung cancer cells . The DNA damage can be repaired by BER or other DNA repair proteins, and cell cytotoxicity and drug resistance can be modulated between these DNA repair pathways.…”

Effect of AICAR and 5-Fluorouracil on X-ray Repair, Cross-Complementing Group 1 Expression, and Consequent Cytotoxicity Regulation in Human HCT-116 Colorectal Cancer Cells

“…It has been reported that AMPK activation and 5-FU synergistically enhanced the antitumor effects of 5-FU on different types of cancer cells [ 17 , 18 , 35 ]. Another study demonstrated that enhancement of the cytotoxicity to cisplatin by administration of curcumin, an anti-inflammatory molecule in the turmeric root, is mediated by the downregulation of the expression levels of XRCC1 in human lung cancer cells [ 36 ]. In this study, inhibition of Akt activation, and CXCR4 and XRCC1 expression by AICAR, enhanced the 5-FU-induced cytotoxicity in CRC cells.…”