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

Ying-Yi Chen,Ming-Jyh Sheu,Yu-Jung Lin,Wei-Ting Huang,Shou-Jen Lan,Dean-Mo Liu,Hui-Yi Lin,Yu-Chen Tu,Chin-Chuan Hung

doi:10.3390/molecules23123217

Abstract

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.

Highlights

Cisplatin-based chemotherapy is the first-line treatment for non-small-cell lung cancer (NSCLC)
transmission electron microscopy (TEM) analysis revealed an increase in size for DMC-carboxymethyl-hexanoyl chitosan (CHC) NPs, with the DMC being randomly distributed as nanocrystals through the CHC phase
In the presence of DMC-CHC NPs, our results showed that this combination treatment significantly decreased both Thymidine phosphorylase (TP) and excision repair cross-complementation 1 (ERCC1) protein expressions when compared to the cisplatin control group (Figure 4A)

Summary

Introduction

Cisplatin-based chemotherapy is the first-line treatment for non-small-cell lung cancer (NSCLC). During the DNA damage of the cancer cells, the NER pathway becomes responsible for repairing bulky lesions [3]. The NER pathway plays important roles by removing cisplatin-induced adducts from the DNA. Excision repair cross-complementation 1 (ERCC1) plays a major role in the incision at the 50 site of damaged DNA [4]. Overexpression of ERCC1 in cancer cells clears the cisplatin-induced DNA adducts, and brings about the drug resistance [4]. Researchers focused on understanding roles of ERCC1 in sensitizing the cisplatin-based chemotherapy for lung cancer. It has been described that the patients with metastatic lung cancer under the treatment of platinum-based chemotherapy benefit from a lower level of ERCC1 [6]. ERCC1 is considered to be one of the significant therapeutic target for lung cancer treatment, as targeting ERCC1 may possibly restore the therapeutic sensitivity to platinum-based chemicals [7]

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