Demethoxycurcumin sensitizes the response of non-small cell lung cancer to cisplatin through downregulation of TP and ERCC1-related pathways

• Published in: Phytomedicine (Stuttgart) Vol. 53; pp. 28 - 36
• Main Authors: Lin, Chen-Yuan, Hung, Chin-Chuan, Wang, Charles C.N., Lin, Hui-Yi, Huang, Shih-Huan, Sheu, Ming-Jyh
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.02.2019
• Subjects: A549 Cells; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cisplatin; Cisplatin - administration & dosage; Cisplatin - pharmacology; Curcuma - chemistry; Curcumin - administration & dosage; Curcumin - analogs & derivatives; Curcumin - chemistry; Curcumin - metabolism; Curcumin - pharmacology; Demethoxycurcumin; Diarylheptanoids; DNA-Binding Proteins - metabolism; Down-Regulation - drug effects; Endonucleases - metabolism; ERCC1; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Molecular Docking Simulation; NSCLC; Phosphatidylinositol 3-Kinases - metabolism; Thymidine Phosphorylase - antagonists & inhibitors; Thymidine Phosphorylase - metabolism; PBS; NSCLC; DMSO; BDMC; HRP; MTT; Cisplatin; ECL; Demethoxycurcumin; CDDP; FITC; ERCC1; NER; DMC; TP
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2018.08.005

•Among curcuminoids, DMC exhibited the most potent cytotoxic effect on A549 cells.•DMC significantly inhibited on-target cisplatin resistance protein, ERCC1, via PI3K-Akt-snail pathways in A549 cells.•DMC significantly inhibited TP in A549 cells.•DMC treatment markedly increased post-target cisplatin resistance pathway in A549 cells.•DMC significantly increased cisplatin-induced cytotoxicity in A549 cells. Excision repair cross-complementary 1 (ERCC1) overexpression in lung cancer cells is strongly correlated with its resistance to platinum-based chemotherapy. Overexpression of thymidine phosphorylase (TP) reverts platinum-induced cancer cell death. Curcumin has been reported to enhance antitumor properties through the suppression of TP and ERCC1 in non-small cell lung carcinoma cells (NSCLC). Nevertheless, whether two other curcuminoids, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) from Curcuma longa demonstrate antitumor activity like that of curcumin remain unknown. MTT assay was conducted to determine the cell cytotoxicity. Western blotting was used to determine the protein expressions. Docking is the virtual screening of a database of compounds and predicting the strongest binders based on various scoring functions. BIOVIA Discovery Studio 4.5 (D.S. 4.5) were used for docking. Firstly, when compared with curcumin and BDMC, DMC exhibited the most potent cytotoxic effect on NSCLC, most importantly, MRC-5, a lung fetal fibroblast, was insensitive to DMC (under 30 µM). Secondly, DMC alone significantly inhibited on-target cisplatin (CDDP) resistance protein, ERCC1, via PI3K-Akt-snail pathways, and TP protein expression in A549 cells. Thirdly, DMC treatment markedly increased post-target CDDP resistance pathway including Bax and cytochrome c. DMC significantly decreased Bcl-2 protein expressions. Finally, MTT assay indicated that DMC significantly increased CDDP-induced cytotoxicity and was confirmed with an increased Bax/Bcl-2 ratio, indicating upregulation of caspase-3. We concluded that enhancement of the cytotoxicity to CDDP by coadminstration with DMC was mediated by down-regulation of the expression of TP and ERCC1, regulated by PI3K-Akt-Snail pathway inactivation. [Display omitted]