Nobiletin Enhances Chemosensitivity to Adriamycin through Modulation of the Akt/GSK3β/β⁻Catenin/MYCN/MRP1 Signaling Pathway in A549 Human Non-Small-Cell Lung Cancer Cells.

Jeong Moon,Somi Cho,Tatsuya Unno,Le Manh Hung

doi:10.3390/nu10121829

Abstract

Drug resistance is a major problem in the treatment of non-small-cell lung cancer (NSCLC). In this study, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed to identify the differentially expressed genes in Adriamycin (ADR)-resistant NSCLC A549/ADR cells compared with parental A549 cells. Among the tested phytochemicals, nobiletin (NBT) is able to overcome the ADR resistance of A549/ADR cells. NBT treatment decreased the expression of a neuroblastoma-derived MYC (MYCN) and multidrug resistance-associated protein 1 (MRP1) as well as downregulating Akt, GSK3β, and β-catenin. Consistent with these results, NBT treatment resulted in the accumulation of intracellular ADR. A combination index (CI) assay confirmed the synergistic effect of combined treatment with NBT and ADR in reducing the viability of A549/ADR cells (CI = 0.152). Combined treatment with NBT and ADR enhanced apoptosis in A549/ADR cells, as evidenced by increased caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, and sub-G1 population compared to treatment with ADR alone. In vivo experiments using a mouse xenograft model revealed that combination therapy with NBT and ADR significantly reduced tumor volume by 84.15%. These data suggest that NBT can sensitize ADR-induced cytotoxicity against A549/ADR cells by inhibiting MRP1 expression, indicating that NBT could serve as an effective adjuvant agent for ADR-based chemotherapy in lung cancer.

Highlights

Lung cancer is one of the most serious cancers worldwide and is the most common malignancy in cancer-related deaths, leading to approximately 1.4 million deaths per year [1]
We examined the induction of apoptosis by ADR in both A540 and A549/ADR cells through cell cycle and Western blot analyses
The cell cycle control system is a major regulator of cell growth, and many cytotoxic agents are known to induce apoptosis through accumulation of the sub-G1 phase

Summary

Introduction

Lung cancer is one of the most serious cancers worldwide and is the most common malignancy in cancer-related deaths, leading to approximately 1.4 million deaths per year [1]. Lung cancer is considered to have the highest incidence and mortality with 1.8 million new cases and 1.6 million new deaths annually [2]. Lung cancers are classified into two major forms, small-cell lung cancer (SCLC). Non-small-cell lung cancer (NSCLC), based on microscopic appearance. NSCLC occurs more frequently and accounts for 85% of all cases of lung cancer [3]. Treatment strategies for lung cancer include radiotherapy, chemotherapy, and surgery [4]. The primary treatment approach for NSCLC is a surgical operation followed by chemotherapy to prevent recurrence [5].

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