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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

by 1,†, 2,†, 1,3 and 1,2,3,*
1
Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea
2
School of Biomaterial Science and Technology, College of Applied Life Sciences, Jeju National University, Jeju 63243, Korea
3
Faculty of Biotechnology, College of Applied Life Sciences, SARI, Jeju National University, Jeju 63243, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Nutrients 2018, 10(12), 1829; https://doi.org/10.3390/nu10121829
Received: 26 October 2018 / Revised: 21 November 2018 / Accepted: 22 November 2018 / Published: 26 November 2018
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. View Full-Text
Keywords: Adriamycin (ADR); A549 human non-small-cell lung cancer cells; multidrug resistance-associated protein 1 (MRP1); nobiletin (NBT) Adriamycin (ADR); A549 human non-small-cell lung cancer cells; multidrug resistance-associated protein 1 (MRP1); nobiletin (NBT)
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MDPI and ACS Style

Moon, J.Y.; Manh Hung, L.V.; Unno, T.; Cho, S.K. 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. Nutrients 2018, 10, 1829. https://doi.org/10.3390/nu10121829

AMA Style

Moon JY, Manh Hung LV, Unno T, Cho SK. 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. Nutrients. 2018; 10(12):1829. https://doi.org/10.3390/nu10121829

Chicago/Turabian Style

Moon, Jeong Y.; Manh Hung, Le V.; Unno, Tatsuya; Cho, Somi K. 2018. "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" Nutrients 10, no. 12: 1829. https://doi.org/10.3390/nu10121829

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