Nobiletin down-regulates c-KIT gene expression and exerts anti-leukemic effects on human acute myeloid leukemia cells. - GreenMedInfo Summary
Nobiletin down-regulates c-KIT gene expression and exerts anti-leukemic effects on human acute myeloid leukemia cells.
J Agric Food Chem. 2018 Dec 3. Epub 2018 Dec 3. PMID: 30507186
Pei-Yi Chen
Nobiletin, a dietary citrus flavonoid, has been reported to possess several biological activities, such as anti-oxidant, anti-inflammatory and anti-cancer properties. The aim of this study was to investigate the anti-leukemic effects of nobiletin and its underlying mechanisms on human acute myeloid leukemia (AML) cells. We demonstrated that nobiletin (0-100μM) 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 μM) 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-KITabolished nobiletin-mediated cell growth inhibition in leukemia cells. These results indicate that nobiletin exerts anti-leukemic 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.