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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Charles C.N. Wang, Hui-Yi Lin, Ming Jyh Sheu, Chin-Chuan Hung, Chen Yuan Lin, and Shih Huan Huang
- Subjects
Curcumin ,Lung Neoplasms ,Down-Regulation ,Pharmaceutical Science ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,chemistry.chemical_compound ,Curcuma ,0302 clinical medicine ,Downregulation and upregulation ,Diarylheptanoids ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Drug Discovery ,medicine ,Humans ,MTT assay ,Cytotoxicity ,030304 developmental biology ,Pharmacology ,A549 cell ,Cisplatin ,Thymidine Phosphorylase ,0303 health sciences ,Chemistry ,Endonucleases ,Antineoplastic Agents, Phytogenic ,DNA-Binding Proteins ,Molecular Docking Simulation ,Complementary and alternative medicine ,A549 Cells ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Molecular Medicine ,ERCC1 ,medicine.drug - 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.
- Published
- 2019