Nobiletin Down-Regulates c-KIT Gene Expression and Exerts Antileukemic Effects on Human Acute Myeloid Leukemia Cells

doi:10.1021/acs.jafc.8b05680

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Title:	Nobiletin Down-Regulates c-KIT Gene Expression and Exerts Antileukemic Effects on Human Acute Myeloid Leukemia Cells
Authors:	Chen, Pei-Yi Chen, Yu-Ting Gao, Wan-Yun Wu, Ming-Jiuan Yen, Jui-Hung
Contributors:	Buddhist Tzu Chi Gen Hosp, Ctr Med Genet Tzu Chi Univ, Dept Mol Biol & Human Genet Chia Nan Univ Pharm & Sci, Dept Biotechnol
Keywords:	nobiletin flavonoid AML c-KIT cytarabine
Date:	2018-12-26
Issue Date:	2019-11-15 15:43:16 (UTC+8)
Publisher:	AMER CHEMICAL SOC
Abstract:	Nobiletin, a dietary citrus flavonoid, has been reported to possess several biological activities such as antioxidant, anti-inflammatory, and anticancer properties. The aim of this study was to investigate the antileukemic effects of nobiletin and its underlying mechanisms on human acute myeloid leukemia (AML) cells. We demonstrated that nobiletin (0-100 mu M) significantly reduced cell viability from 100.0 +/- 9.6% to 31.1 +/- 2.8% in human AML THP-1 cell line. Nobiletin arrested cell cycle progression in G1 phase and induced myeloid cell differentiation in human AML cells. Microarray analysis showed that mRNA expression of the c-KIT gene, a critical proto-oncogene associated with leukemia progression, was dramatically reduced in nobiletin-treated AML cells. Furthermore, we verified that AML cells treated with nobiletin (40 and 80 mu M) for 48 h markedly suppressed c-KIT mRNA expression (from 1.00 +/- 0.07-fold to 0.62 +/- 0.08- and 0.30 +/- 0.05-fold) and reduced the level of c-KIT protein expression (from 1.00 +/- 0.11-fold to 0.60 +/- 0.15- and 0.34 +/- 0.05-fold) by inhibition of KIT promoter activity. The knockdown of c-KIT expression by shRNA attenuated cancer cell growth and induced cell differentiation. Moreover, we found that the overexpression of c-KIT abolished nobiletin-mediated cell growth inhibition in leukemia cells. These results indicate that nobiletin exerts antileukemic effects through the down-regulation of c-KIT gene expression in AML cells. Finally, we demonstrated that the combination of a conventional AML chemotherapeutic agent, cytarabine, with nobiletin resulted in more reduction of cell viability in AML cells. Our current findings suggest that nobiletin is a novel c-KIT inhibitor and may serve as a chemo-preventive or -therapeutic agent against human AML.
???metadata.dc.relation.uri???:	http://dx.doi.org/10.1021/acs.jafc.8b05680
Relation:	International Journal of Medicinal Mushrooms, v.66, n.51, pp.13423-13434
Appears in Collections:	[Dept. of Biotechnology (including master's program)] Periodical Articles

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