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Demethoxycurcumin-Loaded Chitosan Nanoparticle Downregulates DNA Repair Pathway to Improve Cisplatin-Induced Apoptosis in Non-Small Cell Lung Cancer

School of Pharmacy, China Medical University, Hsueh-Hsih Road, Taichung 40402, Taiwan
Department of Pharmacy, Chang Bing Show Chwan Memorial Hospital, No.6, Lugong Rd. Lugang Town, Changhua County 505, Taiwan
Department of Materials Science and Engineering, National Chiao Tung University, 1001 University Road, Hsinchu 300, Taiwan
Department of Healthcare Administration, Asia University, Taichung 41354, Taiwan
Author to whom correspondence should be addressed.
These authors contributed equally.
Academic Editor: Massimiliano Fenice
Molecules 2018, 23(12), 3217;
Received: 13 November 2018 / Revised: 29 November 2018 / Accepted: 4 December 2018 / Published: 5 December 2018
(This article belongs to the Special Issue Advances in Chitin and Chitosan Science)
Demethoxycurcumin (DMC), through a self-assembled amphiphilic carbomethyl-hexanoyl chitosan (CHC) nanomatrix has been successfully developed and used as a therapeutic approach to inhibit cisplatin-induced drug resistance by suppressing excision repair cross-complementary 1 (ERCC1) in non-small cell lung carcinoma cells (NSCLC). Previously, DMC significantly inhibited on-target cisplatin resistance protein, ERCC1, via PI3K-Akt-snail pathways in NSCLC. However, low water solubility and bioavailability of DMC causes systemic elimination and prevents its clinical application. To increase its bioavailability and targeting capacity toward cancer cells, a DMC-polyvinylpyrrolidone core phase was prepared, followed by encapsulating in a CHC shell to form a DMC-loaded core-shell hydrogel nanoparticles (DMC-CHC NPs). We aimed to understand whether DMC-CHC NPs efficiently potentiate cisplatin-induced apoptosis through downregulation of ERCC1 in NSCLC. DMC-CHC NPs displayed good cellular uptake efficiency. Dissolved in water, DMC-CHC NPs showed comparable cytotoxic potency with free DMC (dissolved in DMSO). A sulforhodamine B (SRB) assay indicated that DMC-CHC NPs significantly increased cisplatin-induced cytotoxicity by highly efficient intracellular delivery of the encapsulated DMC. A combination of DMC-CHC NPs and cisplatin significantly inhibited on-target cisplatin resistance protein, ERCC1, via the PI3K-Akt pathway. Also, this combination treatment markedly increased the post-target cisplatin resistance pathway including bax, and cytochrome c expressions. Thymidine phosphorylase (TP), a main role of the pyrimidine salvage pathway, was also highly inhibited by the combination treatment. The results suggested that enhancement of the cytotoxicity to cisplatin via administration of DMC-CHC NPs was mediated by down-regulation of the expression of TP, and ERCC1, regulated via the PI3K-Akt pathway. View Full-Text
Keywords: demethoxycurcumin; chitosan; ERCC1; NSCLC demethoxycurcumin; chitosan; ERCC1; NSCLC
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MDPI and ACS Style

Chen, Y.-Y.; Lin, Y.-J.; Huang, W.-T.; Hung, C.-C.; Lin, H.-Y.; Tu, Y.-C.; Liu, D.-M.; Lan, S.-J.; Sheu, M.-J. Demethoxycurcumin-Loaded Chitosan Nanoparticle Downregulates DNA Repair Pathway to Improve Cisplatin-Induced Apoptosis in Non-Small Cell Lung Cancer. Molecules 2018, 23, 3217.

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