5-Demethylnobiletin Inhibits Cell Proliferation, Downregulates ID1 Expression, Modulates the NF-κB/TNF-α Pathway and Exerts Antileukemic Effects in AML Cells

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Title:	5-Demethylnobiletin Inhibits Cell Proliferation, Downregulates ID1 Expression, Modulates the NF-κB/TNF-α Pathway and Exerts Antileukemic Effects in AML Cells
Authors:	Chen, Pei-Yi Wang, Chih-Yang Tsao, En-Ci Chen, Yu-Ting Wu, Ming-Jiuan Ho, Chi-Tang Yen, Jui-Hung
Contributors:	Buddhist Tzu Chi General Hospital Hualien Tzu Chi Hospital Tzu Chi University Taipei Medical University Taipei Medical University Department of Biotechnology, Chia Nan University of Pharmacy & Science Rutgers System Rutgers New Brunswick Tzu Chi University
Keywords:	cancer polymethoxyflavones proteins citrus carcinogenesis metabolites apoptosis nobiletin promotes drugs
Date:	2022
Issue Date:	2023-12-11 14:00:18 (UTC+8)
Publisher:	MDPI
Abstract:	Acute myeloid leukemia (AML) is characterized by the dysregulation of hematopoietic cell proliferation, resulting in the accumulation of immature myeloid cells in bone marrow. 5-Demethylnobiletin (5-demethyl NOB), a citrus 5-hydroxylated polymethoxyflavone, has been reported to exhibit various bioactivities, such as antioxidant, anti-inflammatory and anticancer properties. In this study, we investigated the antileukemic effects of 5-demethyl NOB and its underlying molecular mechanisms in human AML cells. We found that 5-demethyl NOB (20-80 mu M) significantly reduced human leukemia cell viability, and the following trend of effectiveness was observed: THP-1 approximate to U-937 > HEL > HL-60 > K562 cells. 5-Demethyl NOB (20 and 40 mu M) modulated the cell cycle through the regulation of p21, cyclin E1 and cyclin A1 expression and induced S phase arrest. 5-Demethyl NOB also promoted leukemia cell apoptosis and differentiation. Microarray-based transcriptome, Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) of differentially expressed genes (DEGs) analysis showed that the expression of inhibitor of differentiation/DNA binding 1 (ID1), a gene associated with the GO biological process (BP) cell population proliferation (GO: 0008283), was most strongly suppressed by 5-demethyl NOB (40 mu M) in THP-1 cells. We further demonstrated that 5-demethyl NOB-induced ID1 reduction was associated with the inhibition of leukemia cell growth. Moreover, DEGs involved in the hallmark gene set NF-kappa B/TNF-alpha signaling pathway were markedly enriched and downregulated by 5-demethyl NOB. Finally, we demonstrated that 5-demethyl NOB (20 and 40 mu M), combined with cytarabine, synergistically reduced THP-1 and U-937 cell viability. Our current findings support that 5-demethyl NOB dramatically suppresses leukemia cell proliferation and may serve as a potential phytochemical for human AML chemotherapy.
Relation:	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v.23, n.13, 7392CB2
Appears in Collections:	[Dept. of Biotechnology (including master's program)] Periodical Articles

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