Demethoxycurcumin sensitizes the response of non-small cell lung cancer to cisplatin through downregulation of TP and ERCC1-related pathways.
Phytomedicine
; 53: 28-36, 2019 Feb.
Article
en En
| MEDLINE
| ID: mdl-30668408
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.
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Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Protocolos de Quimioterapia Combinada Antineoplásica
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Carcinoma de Pulmón de Células no Pequeñas
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Curcumina
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Proteínas de Unión al ADN
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Endonucleasas
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Neoplasias Pulmonares
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Phytomedicine
Año:
2019
Tipo del documento:
Article
País de afiliación:
Taiwán