Nobiletin suppresses the proliferation and induces apoptosis involving MAPKs and caspase-8/-9/-3 signals in human acute myeloid leukemia cells

Hsiao, Pei Ching; Lee, Wei-Jiunn; Yang, Shun Fa; Tan, Peng; Chen, Hui-Yu; Lee, Liang‐Ming; Chang, Junn Liang; Lai, Gabriel Y.; Chow, Julie Chi; Chien, Ming‐Hsien

doi:10.1007/s13277-014-2457-0

Cited by 36 publications

(33 citation statements)

References 40 publications

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“…Aoki et al [99] found that nobiletin suppresses the cell proliferation by inhibiting Ras activity and MEK/ERK signaling cascade probably via a Ca 2+ -sensitive PKC-dependent mechanism. Hsiao et al [100] also reported that nobiletin suppressed cell proliferation in HL-60 AML cells via inducing cell-cycle arrest at the G0/G1 phase by suppressing extracellular signal-regulated kinase (ERK) activity. In another study, the nobiletin was shown to inhibit the proliferation of human pancreatic cancer cells (PANC-1) by inducing apoptosis via up-regulation of the proapoptotic protein bax and down-regulation of the anti-apoptotic proteins bcl-2 and p53 [101].…”

Section: Anti-proliferationmentioning

confidence: 99%

Citrus Flavonoids and Human Cancers

Ke¹,

Pan²,

Xu³

et al. 2015

JFNR

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Nowadays cancers pose a great threat to the health of human beings. Based on studies on the flavonoids and other bioactive compounds of Citrus fruits in current literature, it was widely suggested that the consumption of Citrus fruits is beneficial to the prevention and treatment of human chronic diseases including cancers. In the past decades, the study concerning Citrus flavonoids has covered various areas including the type, content and distribution of flavonoids in fruits; their variation between wild and cultivated genotypes; their antioxidant, antiinflammation, anti-aging, antimicrobial and anticarcinogenic activities. To enlighten future Citrus germplasm study, this review introduces briefly the functions of main types of Citrus flavonoids, including antioxidant, antiinflammation and anti-aging activities, and their relationships to human cancers. Most importantly, the mechanisms of action by which Citrus flavonoids play their roles in human cancer prevention and treatment were summarized.

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Section: Anti-proliferationmentioning

confidence: 99%

Citrus Flavonoids and Human Cancers

Ke¹,

Pan²,

Xu³

et al. 2015

JFNR

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“…Flavonoids, a vast group of polyphenolic compounds ubiquitously present in plants [17], exhibit a wild spectrum of pharmacological properties and offer significantly protection against various cancers [18, 19]. As a member of flavonoids, nobiletin (5, 6, 7, 8, 3′ 4′-hexamethoxyflavone) has been proposed to have anti-cancer properties, including anti-angiogenesis, anti-proliferation, anti-metastasis and induced apoptosis in vitro and in vivo [20–23]. Accumulate studies have showed that nobiletin also suppressed the expression of MMPs, which may serve as a promising agent for suppression of cancer invasion and metastasis [24].…”

Section: Introductionmentioning

confidence: 99%

Nobiletin inhibits human osteosarcoma cells metastasis by blocking ERK and JNK-mediated MMPs expression

et al. 2016

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Nobiletin, a polymethoxyflavone, has a few pharmacological activities, including anti-inflammation and anti-cancer effects. However, its effect on human osteosarcoma progression remains uninvestigated. Therefore, we examined the effectiveness of nobiletin against cellular metastasis of human osteosarcoma and the underlying mechanisms. Nobiletin, up to 100 μM without cytotoxicity, significantly decreased motility, migration and invasion as well as enzymatic activities, protein levels and mRNA expressions of matrix metalloproteinase (MMP)-2 and MMP-9 in U2OS and HOS cells. In addition to inhibition of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), the inhibitory effect of nobiletin on the DNAbinding activity of the transcription factor nuclear factor-kappa B (NF-κB), cAMP response element-binding protein (CREB), and specificity protein 1 (SP-1) in U2OS and HOS cells. Co-treatment with ERK and JNK inhibitors and nobiletin further reduced U2OS cells migration and invasion. These results indicated that nobiletin inhibits human osteosarcoma U2OS and HOS cells motility, migration and invasion by downregulating MMP-2 and MMP-9 expressions via ERK and JNK pathways and through the inactivation of downstream NF-κB, CREB, and SP-1. Nobiletin has the potential to serve as an anti-metastatic agent for treating osteosarcoma.

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“…), suppresses tumor proliferation (SMMC-7721, DU145, MDA-MB-435, MCF-7, HT29, and HTB43 cells, etc. ), and inhibits metastasis of tumor cells (HT-1080) [6,7,8,9,10,11,12,13,14]. Nobiletin also suppresses angiogenesis in human umbilical vein endothelial cells in vitro and in chicken chorioallantoic membrane and zebrafish in vivo models [15,16].…”

Section: Introductionmentioning

confidence: 99%

Nobiletin Relaxes Isolated Mesenteric Arteries by Activating the Endothelial Ca2+-eNOS Pathway in Rats

Yang

Lin

et al. 2016

J Vasc Res

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Aims: Nobiletin, a natural polymethoxylated flavonoid compound, has various beneficial properties, such as anticancer, anti-inflammatory, and antioxidant effects, and it also improves memory. Therefore, we investigated the effects and mechanisms of nobiletin on rat isolated mesenteric arteries (MAs). Methods: We examined vasodilation induced by nobiletin on rat isolated MA rings with a tension study, the expression and activity of endothelial nitric oxide synthase (eNOS) with Western blotting, NO production with DAF- FMDA fluorescence, and intracellular Ca²⁺ concentration ([Ca²⁺]i) with Fluo-3AM. Results and Conclusion: Our study showed that nobiletin elicited a dose-dependent vasodilation in phenylephrine precontracted MA rings, but it did not elicit the same response in pulmonary artery rings. Vasodilation was related to endothelium and activated partly by eNOS. Vasodilation was inhibited by denudation of the endothelium or inhibition of eNOS activity. Nobiletin increased NO production by promoting the phosphorylation of eNOS at Ser-1177 without changing the level of eNOS expression in rat mesenteric artery endothelial cells (RMAECs). Nobiletin increased the concentration of endothelial [Ca²⁺]i, which enhances eNOS activity in RMAECs. In summary, vasodilation induced by nobiletin was dependent on the endothelium and partly on eNOS activation, which is mediated by high endothelial [Ca²⁺]i. Results suggest nobiletin may offer a therapeutic benefit and could potentially be used as a vasodilator for the treatment of hypertension.

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Nobiletin suppresses the proliferation and induces apoptosis involving MAPKs and caspase-8/-9/-3 signals in human acute myeloid leukemia cells

Cited by 36 publications

References 40 publications

<i>Citrus</i> Flavonoids and Human Cancers

<i>Citrus</i> Flavonoids and Human Cancers

Nobiletin inhibits human osteosarcoma cells metastasis by blocking ERK and JNK-mediated MMPs expression

Nobiletin Relaxes Isolated Mesenteric Arteries by Activating the Endothelial Ca<sup>2+</sup>-eNOS Pathway in Rats

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