Nootkatone, an AMPK activator derived from grapefruit, inhibits KRAS downstream pathway and sensitizes non-small-cell lung cancer A549 cells to adriamycin

Hung, Le Van; Moon, Jeong Yong; Ryu, Ji-Yeon; Cho, Somi Kim

doi:10.1016/j.phymed.2019.153000

Cited by 34 publications

(29 citation statements)

References 22 publications

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“…The suppression of cyclin D1 and induction of NAG-1 by nootkatone were observed at a concentration of 100 μM. A similar result was reported in lung cancer cells where 100 μM of nootkatone was required to obtain cell growth inhibition [8]. Since the systemic concentration of nootkatone and its concentration in tissues has not been reported, and most phytochemicals could reach even higher concentrations in the gastrointestinal (GI) track, the speculation that nootkatone probably reaches 100 μM in the GI track is reasonable.…”

Section: Discussionsupporting

confidence: 80%

“…Additionally, nootkatone increased survival rates in septic mice by increasing HO-1 expression [25]. Although nootkatone has been linked to anticancer activity in lung cancer via the AMPK pathway [8], the effects of nootkatone against colorectal cancer and its mechanisms underlying these effects remain unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Amongst them, nootkatone is one of the more abundant components [6]. Nootkatone has also been identified as the main fragrant component of grapefruit with a wide range of beneficial effects including anti-inflammation activities [7], AMPK activation [8] and neuroprotective effects [9]. Other bioactive compounds in A. oxyphylla, yakuchinone A [10] and yakuchinone B [11], are also known to have several biological activities including anti-cancer activity.…”

Section: Introductionmentioning

confidence: 99%

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Anti-proliferative activity of A. Oxyphylla and its bioactive constituent nootkatone in colorectal cancer cells

et al. 2020

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Background A. oxyphylla extract is known to possess a wide range of pharmacological activites. However, the molecular mechanism of A. oxyphylla and its bioactive compound nootkatone in colorectal cancer is unknown. Methods Our study aims to examine the role of A. oxyphylla and its bioactive compound nootkatone, in tumor suppression using several in vitro assays. Results Both A. oxyphylla extract and nootkatone exhibited antiproliferative activity in colorectal cancer cells. A. oxyphylla displayed antioxidant activity in colorectal cancer cells, likely mediated via induction of HO-1. Furthermore, expression of pro-apoptotic protein NAG-1 and cell proliferative protein cyclin D1 were increased and decreased respectively in the presence of A. oxyphylla. When examined for anticancer activity, nootkatone treatment resulted in the reduction of colony and spheroid formation. Correspondingly, nootkatone also led to increased NAG-1 expression and decreased cyclin D1 expression. The mechanism by which nootkatone suppresses cyclin D1 involves protein level regulation, whereas nootkatone increases NAG-1 expression at the transcriptional level. In addition to having PPARγ binding activity, nootkatone also increases EGR-1 expression which ultimately results in enhanced NAG-1 promoter activity. Conclusion In summary, our findings suggest that nootkatone is an anti-tumorigenic compound harboring antiproliferative and pro-apoptotic activity.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anti-proliferative activity of A. Oxyphylla and its bioactive constituent nootkatone in colorectal cancer cells

et al. 2020

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“…Aside the obvious interest by the flavour and fragrance industry in the production and application of these two compounds, [71,72] themselves or their derivatives were potential repellent insecticides [72][73][74][75][76] and especially the bioactivity of 2 encompasses useful properties such as anticarcinogenic activity. [77][78][79] In contrast, terpene 3 is less volatile and hence odourless, and found to be active against parasitic worms. [80] Natural product 1 was hydroxylated by P450 3A4 at positions 5 and 6 trans to the sterically demanding isopropyl substituent, which occupies the equatorial position in a preferred half-chair confirmation, [81] according to the NMR data of isolated material and at position 7 by comparison to an authentic reference (Scheme 2A).…”

Section: Resultsmentioning

confidence: 99%

Natural Product Diversification by One‐Step Biocatalysis using Human P450 3A4

et al. 2021

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Efficient synthetic techniques for the diversification of natural products are incremental for drug discovery processes of the pharmaceutical industry because these complex bioactive compounds often require an adjustment of properties. Human liver P450 3A4, key player of the body's detoxification system and decisive factor of a drug's metabolic fate, is renowned for its broad substrate scope including many natural products. In this study, we investigated the synthetic potential of human P450 3A4 for the diversification of natural product classes and isolated the produced metabolites of six selected natural products at a preparative 100-mg scale. Aided by efficient expression levels in P. pastoris, this whole-cell biocatalyst was found to be highly effective at the intended job allowing the identification of a total of 31 authentic human metabolites, many of them for the first time. By revealing an unprecedented degree of diversification, this study extends the synthetic repertoire for efficient enzymatic natural product modification in a one-step fashion and adds a completely new view to an old enzyme traditionally used for inhibition and toxicology studies.

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“…However, the role of stigmasterol in lung cancer was rarely reported. Nootkatone inhibited growth of A549 cells and induced G1 cell cessation by activating AMPK via LKB1-independent and CAMKK2-dependent pathways [36]. Ergotamine was a vasoconstricting agent, which could cause toxicity and inhibit tumor growth [37].…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology and Experiment Verification to Explore the Potential Mechanism of Yin-Huo-Tang for Lung Adenocarcinoma Recurrence

Liu

Lin

et al. 2021

Preprint

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BackgroundLung adenocarcinoma (LUAD) is one of the most common malignancies with a rise in new cases worldwide each year. Recurrence significantly influences the survival in patients with LUAD. Yin-Huo-Tang (YHT) is a classic traditional Chinese prescription, used to prevent lung cancer relapse by “nourishing yin and clearing heat”. MethodsIn this study, the mechanism of YHT in LUAD recurrence was investigated. Firstly, the bioactive compounds-targets network and the protein–protein interaction network were constructed, and functional annotation and pathway enrichment analyses were performed. Pivotal compounds and hub genes were selected from the networks. Subsequently, the effectiveness of YHT was confirmed in lewis lung carcinoma mice. RNA sequencing was used to explore the mRNA expression differences between tumor tissues in the model mouses and YHT-treated mouses. The pathways screened by network pharmacology and RNA sequencing analysis at the same time were considered the most important pathways. At last, qualitative phytochemical analysis, molecular docking technology, PCR and WB analysis were used to validate the pivotal active ingredients, hub genes and main pathways.ResultsThere were 128 active compounds, 419 targets interacting with LUAD recurrence. Network analysis identified 4 pivotal compounds, 28 hub genes and 30 main pathways. Target genes mainly focused on inflammation, metabolism, immune responses and apoptosis. We confirmed that YHT could inhibit the recurrence of lung adenocarcinoma through animal experimental study. Sphingolipid signaling pathway was the common main pathway in network pharmacology and RNA sequencing results. The hub genes related with the sphingolipid signaling pathway was S1PR5. Qualitative phytochemical analysis of the water extract of YHT confirmed the presence of 3 pivotal compounds, namely stigmasterol, nootkatone and ergotamine. The results of molecular docking verified the pivotal compounds of YHT could good affinity with the S1PR5. The PCR and WB analysis verified YHT suppressed lewis lung cancer cells proliferation by inhibiting S1P/S1PR5/Gi/Ras/Raf/MEK/ERK pathway, and inhibited migration through S1P/S1PR5/Gi/PI3K/RAC pathway.ConclusionThe results confirmed the therapeutic effect of YHT on the recurrence of LUAD by multi-component-multi-target mode, the sphingolipid signaling pathway was one of the most relevant potential signaling pathways.

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Nootkatone, an AMPK activator derived from grapefruit, inhibits KRAS downstream pathway and sensitizes non-small-cell lung cancer A549 cells to adriamycin

Cited by 34 publications

References 22 publications

Anti-proliferative activity of A. Oxyphylla and its bioactive constituent nootkatone in colorectal cancer cells

Anti-proliferative activity of A. Oxyphylla and its bioactive constituent nootkatone in colorectal cancer cells

Natural Product Diversification by One‐Step Biocatalysis using Human P450 3A4

Network Pharmacology and Experiment Verification to Explore the Potential Mechanism of Yin-Huo-Tang for Lung Adenocarcinoma Recurrence

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