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

Chen-Yuan Lin, Chin Chuan Hung, Charles C.N. Wang, Hui Yi Lin, Shih Huan Huang, Ming Jyh Sheu

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)28-36
Number of pages9
JournalPhytomedicine
Volume53
DOIs
StatePublished - Feb 1 2019

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Thymidine Phosphorylase
Non-Small Cell Lung Carcinoma
DNA Repair
Cisplatin
Down-Regulation
Curcumin
Snails
Platinum
Phosphatidylinositol 3-Kinases
Proteins
Curcuma
demethoxycurcumin
Cytochromes c
Caspase 3
Lung Neoplasms
Cell Death
Up-Regulation
Fibroblasts
Western Blotting
Databases

Keywords

  • Cisplatin
  • Demethoxycurcumin
  • ERCC1
  • NSCLC
  • TP

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine

Cite this

Demethoxycurcumin sensitizes the response of non-small cell lung cancer to cisplatin through downregulation of TP and ERCC1-related pathways. / Lin, Chen-Yuan; Hung, Chin Chuan; Wang, Charles C.N.; Lin, Hui Yi; Huang, Shih Huan; Sheu, Ming Jyh.

In: Phytomedicine, Vol. 53, 01.02.2019, p. 28-36.

Research output: Contribution to journalArticle

Lin, Chen-Yuan ; Hung, Chin Chuan ; Wang, Charles C.N. ; Lin, Hui Yi ; Huang, Shih Huan ; Sheu, Ming Jyh. / Demethoxycurcumin sensitizes the response of non-small cell lung cancer to cisplatin through downregulation of TP and ERCC1-related pathways. In: Phytomedicine. 2019 ; Vol. 53. pp. 28-36.
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AU - Lin, Chen-Yuan

AU - Hung, Chin Chuan

AU - Wang, Charles C.N.

AU - Lin, Hui Yi

AU - Huang, Shih Huan

AU - Sheu, Ming Jyh

PY - 2019/2/1

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AB - 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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