1. Demethoxycurcumin sensitizes the response of non-small cell lung cancer to cisplatin through downregulation of TP and ERCC1-related pathways.
- Author
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Lin CY, Hung CC, Wang CCN, Lin HY, Huang SH, and Sheu MJ
- Subjects
- A549 Cells, Antineoplastic Agents, Phytogenic administration & dosage, Antineoplastic Agents, Phytogenic pharmacology, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Cisplatin administration & dosage, Cisplatin pharmacology, Curcuma chemistry, Curcumin administration & dosage, Curcumin chemistry, Curcumin metabolism, Curcumin pharmacology, Diarylheptanoids, Down-Regulation drug effects, Humans, Lung Neoplasms metabolism, Lung Neoplasms pathology, Molecular Docking Simulation, Phosphatidylinositol 3-Kinases metabolism, Thymidine Phosphorylase antagonists & inhibitors, Thymidine Phosphorylase metabolism, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, Curcumin analogs & derivatives, DNA-Binding Proteins metabolism, Endonucleases metabolism, Lung Neoplasms drug therapy
- Abstract
Background: 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., Purpose: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2018 Elsevier GmbH. All rights reserved.)
- Published
- 2019
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