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Nobiletin Enhances Chemosensitivity to Adriamycin through Modulation of the Akt/GSK3?/??Catenin/MYCN/MRP1 Signaling Pathway in A549 Human Non-Small-Cell Lung Cancer Cells.

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, GSK3?, and ?-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.

SUBMITTER: Moon JY

PROVIDER: S-EPMC6316077 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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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.

Moon Jeong Yong JY Manh Hung Le Van LV Unno Tatsuya T Cho Somi Kim SK

Nutrients 20181126 12

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) ...[more]

PMID: 30486290

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Project description:Cacumen Platycladi (CP) consists of the dried needles of Platycladus orientalis L.) Franco. It was clinically demonstrated that it effectively regenerates hair, but the underlying mechanism remains unknown. Thus, we employed shaved mice to verify the hair growth-promoting capability of the water extract of Cacumen Platycladi (WECP). The morphological and histological analyses revealed that WECP application could significantly promote hair growth and hair follicles (HFs) construction, in comparison to that of control group. Additionally, the skin thickness and hair bulb diameter were significantly increased by the application of WECP in a dose-dependent manner. Besides, the high dose of WECP also showed an effect similar to that of finasteride. In an in vitro assay, WECP stimulated dermal papilla cells (DPCs) proliferation and migration. Moreover, the upregulation of cyclins (cyclin D1, cyclin-dependent kinase 2 (CDK2), and cyclin-dependent kinase 4 (CDK4)) and downregulation of P21 in WECP-treated cell assays have been evaluated. We identified the ingredients of WECP using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) and endeavored to predict their relevant molecular mechanisms by network analysis. We found that the Akt (serine/threonine protein kinase) signaling pathway might be a crucial target of WECP. It has been demonstrated that WECP treatment activated the phosphorylation of Akt and glycogen synthase kinase-3-beta (GSK3β), promoted β-Catenin and Wnt10b accumulation, and upregulated the expression of lymphoid enhancer-binding factor 1 (LEF1), vascular endothelial growth factor (VEGF), and insulin-like growth factor 1 (IGF1). We also found that WECP significantly altered the expression levels of apoptosis-related genes in mouse dorsal skin. The enhancement capability of WECP on DPCs proliferation and migration could be abrogated by the Akt-specific inhibitor MK-2206 2HCl. These results suggested that WECP might promote hair growth by modulating DPCs proliferation and migration through the regulation of the Akt/GSK3β/β-Catenin signaling pathway.

Dataset Information

Nobiletin Enhances Chemosensitivity to Adriamycin through Modulation of the Akt/GSK3?/??Catenin/MYCN/MRP1 Signaling Pathway in A549 Human Non-Small-Cell Lung Cancer Cells.

Publications

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.

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