Nobiletin is a phytochemical found abundantly in citrus peels.[1]
Most abundantly found in tangerines sweet orange peel (Citrus sinensis) and in bitter orange peel (Citrus aurantium).[2]
Composition / Absorption
Nobiletin is a citrus flavonoid with multiple methoxy groups that has a poor water solubility and low oral bioavailability.[1:1]
- Flavonoids are a class of chemically related polyphenols that are nearly ubiquitous in nature.[2:1]
Biological Properties
Nobiletin has been demonstrated to possess a broad spectrum of bioactivities, including anti-inflammatory, anti-atherogenic, neuroprotective, and anti-tumor properties.
Anti-Cancer
Nobelitin has been reported to exert anti-proliferative properties in several cancer cell lines.[1:2]
- Nobiletin shows inhibition of cell proliferation and invasion, arrest of cell cycle progression or induction of cell apoptosis in various types of solid tumors.[1:3]
Anti-Leukemic
Nobelitin inhibites cancer cell growth, modulates cell cycle progression and inducing K562 cells toward megakaryocyte differentiation.
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In hematological malignancies, Nobiletin was shown to suppress cell growth and induce caspase-dependent apoptosis in human acute myeloid leukemia cells.[1:4]
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Modulates cell differentiation of leukemia cells and exerted anti-leukemic effects through downregulation of the c-KIT gene.[1:5]
Cardiovascular Health (Heart Health)
Antilipidemic (Antihyperlipidemic)
Citrus flavonoids have the potential to help lower cholesterol.
Citrus fruit-derived flavonoids are suggested to have an inverse association with the occurrence of coronary heart disease via their ability to reduce plasma cholesterol concentrations.[2:2]
- Citrus flavonoids could reduce the occurrence of cardiovascular disease through their ability to reduce hepatic production of cholesterol containing lipoproteins, and hence reduce total plasma cholesterol concentrations.[2:3]
In addition to reducing plasma cholesterol concentrations, nobiletin may prevent atherosclerosis at the level of the vascular wall by inhibiting macrophage foam-cell formation.[2:4]
Disease / Symptom Treatment
Chronic myeloid leukemia (CML)
Nobelitin may serve as a novel therapeutic agent for patients with CML.[1:6]
- Nobelitin possessed the anti-leukemic ability to reduce cell viability, inhibit cell growth, arrest cell cycle in G1 phase, and induce megakaryocyte differentiation of K562 cells.[1:7]
- Nobelitin promoted megakaryocytic differentiation through the activation of MAPK/ERK pathway-dependent EGR1 expression in K562 cells.[1:8]
- When Nobelitin was combined with imatinib (chemotherapeutic agent) could synergistically reduce the viability of K562 cells.[1:9]
Heart Disease
Atherosclerosis
Nobelitin helps reduce plasma cholesterol concentrations and inhibites macrophage foam-cell formation.[2:5]
Adverse Affects
Nobelitin has been reported to be nongenotoxic.[1:10]
Synergistic Effects
- Nobelitin demonstrated a synergistic effect of reducing the viability of K562 (leukemia) cells when combined with imatinib (chemotherapeutic drug) treatment.[1:11]
Study Type: Human Study: In Vitro, Review
Title: Nobiletin Promotes Megakaryocytic Differentiation through the MAPK/ERK-Dependent EGR1 Expression and Exerts Anti-Leukemic Effects in Human Chronic Myeloid Leukemia (CML) K562 Cells
Author(s): Jui-Hung Yen, Ching-Yen Lin, Chin-Hsien Chuang, Hsien-Kuo Chin, Ming-Jiuan Wu, and Pei-Yi Chen
Institution(s): Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan; Division of Cardiovascular, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan; Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan; Center of Medical Genetics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan
Publication: MDPI: Cells
Date: 3 April 2020
Abstract: Differentiation therapy is an alternative strategy used to induce the differentiation of blast cells toward mature cells and to inhibit tumor cell proliferation for cancer treatment. Nobiletin (NOB), a polymethoxyflavone phytochemical, is present abundantly in citrus peels and has been reported to possess anti-cancer activity. In this study, we investigated the anti-leukemic effects of NOB on cell differentiation and its underlying mechanisms in human chronic myeloid leukemia (CML) K562 cells. NOB (100 μM) treatment for 24 and 48 h significantly decreased viability of K562 cells to 54.4 ± 5.3% and 46.2 ± 9.9%, respectively. NOB (10–100 μM) significantly inhibited cell growth in K562 cells. Flow cytometry analysis and immunoblotting data showed that NOB (40 and 80 μM) could modulate the cell cycle regulators including p21, p27, and cyclin D2, and induce G1 phase arrest. NOB also increased the messenger RNA (mRNA) and protein expression of megakaryocytic differentiation markers, such as CD61, CD41, and CD42 as well as the formation of large cells with multi-lobulated nuclei in K562 cells. These results suggested that NOB facilitated K562 cells toward megakaryocytic differentiation. Furthermore, microarray analysis showed that expression of EGR1, a gene associated with promotion of megakaryocytic differentiation, was markedly elevated in NOB-treated K562 cells. The knockdown of EGR1 expression by small interference RNA (siRNA) could significantly attenuate NOB-mediated cell differentiation. We further elucidated that NOB induced EGR1 expression and CD61 expression through increases in MAPK/ERK phosphorylation in K562 cells. These results indicate that NOB promotes megakaryocytic differentiation through the MAPK/ERK pathway-dependent EGR1 expression in human CML cells. In addition, NOB when combined with imatinib could synergistically reduce the viability of K562 cells. Our findings suggest that NOB may serve as a beneficial anti-leukemic agent for differentiation therapy.
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Title: Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class A scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages
Author(s): Stewart C.Whitman, Elzbieta M. Kurowska, John A.Manthey, Alan Daugherty
Institution(s): Laboratory Medicine and Cellular and Molecular Medicine, Departments of Pathology, University of Ottawa Heart Institute, 40 Ruskin St., Room H259A, Ottawa, Ont., Canada K1Y 4W7; KGK Synergize Inc., London, Ont., Canada; USDA, ARS, Winter Haven, FL, USA; Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY, USA
Publication: Atherosclerosis
Date: January 2005
Abstract: Flavonoids are a class of chemically related polyphenols that are nearly ubiquitous in nature. Of the more-than 4000 flavonoids thus identified, citrus fruit-derived flavonoids are suggested to have an inverse association with the occurrence of coronary heart disease via their ability to reduce plasma cholesterol concentrations. Our current studies examined whether citrus flavonoids possess an additional antiatherogenic effect by modulating macrophage metabolism of the specific class A scavenger receptor (SR-A) ligand, acetylated LDL (acLDL). In this study, both acLDL-metabolism and SR-A expression by cultured murine J774A.1 macrophages was examined following 24 h pretreatment (100 μM) with the flavonoids: naringenin (from grapefruit), hesperetin (from oranges), and tangeretin and nobiletin (from tangerines). Of these flavonoids, only nobiletin inhibited (50–72%) acLDL metabolism as measured by both cellular cholesterol ester mass and [3H]oleate incorporation into cholesterol esters. This nobiletin-mediated effect was specific for SR-A and not a global effect on lipoprotein metabolism by the macrophage, as all four citrus flavonoids significantly reduce the metabolism of beta-VLDL, which is primarily taken up by macrophages via the LDL receptor. Nevertheless, nobiletin did not affect SR-A protein expression, as measured by Western blot analysis, nor was cell surface expression of SR-A affected as measured by 4 °C binding studies using [125I]acLDL. In conclusion, our findings suggest that in addition to reducing plasma cholesterol concentrations, nobiletin may prevent atherosclerosis at the level of the vascular wall by inhibiting macrophage foam-cell formation.
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