The Flavonol Isoquercitrin Promotes Mitochondrial-Dependent Apoptosis in SK-Mel-2 Melanoma Cell via the PI3K/AKT/mTOR Pathway

Won, Yeong Seon; Kim, Jeong-Ho; Lizardo, Rona Camille M.; Min, Hye Ji; Cho, Hyun Dong; Hong, Seong Min; Seo, Kwon Il

doi:10.3390/nu12123683

Cited by 27 publications

(18 citation statements)

References 29 publications

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Section: Resultsmentioning

confidence: 99%

“…78 It should also be mentioned that PI3K/RAC alpha serine/threonine protein kinase (AKT)/mTOR signaling pathway has been shown to be over-activated in some types of skin cancers, 80 with the anti-proliferative activity of some phenolic compounds against SK-MEL-2 cancer cells attributed to the downregulation of the PI3K/AKT/mTOR signaling pathway, which induces a mitochondrial-dependent apoptosis. 81 Other potential targets revealed during the in silico "target fishing" reverse screening, including Poly(ADPribose)polymerase (PARP), 82,83 phosphodiesterase type 5, 84,85 orphan nuclear receptor LRH-1, 86,87 nuclear receptor ROR-gamma, 88,89 matrix metallopeptidase 9 (MMP9), 90 NAD-dependent deacetylase Sirtuin 2, 91 and cholesterol ester transfer protein, 92 all believed to play important roles in skin carcinogenesis. There is no doubt that the wealth of information gathered here will be useful in further studies towards the optimizing the hit molecules' activity and determining their putative drug target and potential mechanism(s) of action.…”

Section: In Silico Target(s) Prediction Pharmacokinetic and Admet Stu...mentioning

confidence: 99%

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Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds

Boateng

Roy

Agbo

et al. 2022

Preprint

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Melanoma and nonmelanoma skin cancer are the most lethal and commonest forms of skin cancers affecting one fifth of the US population. With the aim of identifying new lead compounds as starting point for attaining cost effective therapies, a small library of about 90 molecules was screened in vitro against A375, SKMEL28, A431, SCC12 skin cancer cell lines. About 35 of them, mainly dihydroquinolines, CC and CN linked biphenyls, and substituted methyl gallate or aniline derivatives, displayed low micromolar range activities, primarily against the A431 and SCC12 squamous carcinoma cell lines, with only a handful of these compounds displaying any activity against the A375 and SKMEL28 melanoma cell lines. Compounds 11 (A431: IC50 = 5.0 lower case Greek muM, SCC12: IC50 = 2.9 lower case Greek muM, SKMEL-28: IC50 = 4.9 lower case Greek muM, A375: IC50 = 6.7 lower case Greek muM) and 13 (A431: IC50 = 5.0 lower case Greek muM, SCC-12: IC50 = 3.3 lower case Greek muM, SKMEL-28: IC50 = 13.8 lower case Greek muM, A375: IC50 = 17.1 lower case Greek muM) were the most active across all these cell lines. Furthermore, many of the hit compounds showed little to no activity against mammalian nontumorigenic immortalized HaCaT cells, with a far better selectivity index than cisplatin (a well-known anticancer agent used as a positive control). Compounds 11 and 13 significantly and dose dependently induced apoptosis of SCC12 and SKMEL28 cells as evidenced by the downregulation of Bcl2 and upregulation of Bax protein expression levels, and by cleaved caspase 3, caspase 9 and PARP levels. Both agents also significantly reduced scratch wound healing, colony formation, and activated expression levels of major cancer molecular targets such as RSK/AKT/ERK1/2 and S6K1. To provide a better attribute profile for each of the hit molecules, in silico target(s) prediction, pharmacokinetic and ADMET studies are also reported, together with some preliminary structure activity relationship outlines. The SwissTargetPrediction web-based tool identified CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, as likely targets for these hit compounds. Furthermore, the SwissADME web_tool predicted these compounds to exhibit high GI tract absorption, good skin permeation, and a viable biodegradability profile. To summarize, these data highlight the promising anticancer potential of these small molecules leads, warranting further investigation and/or optimization towards obtaining clinical candidates for combatting both melanoma and nonmelanoma skin cancers.

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Section: Resultsmentioning

confidence: 99%

Section: In Silico Target(s) Prediction Pharmacokinetic and Admet Stu...mentioning

confidence: 99%

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds

Boateng

Roy

Agbo

et al. 2022

Preprint

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“…[26] Isoquercitrin was stated to have some important biological functions, such as antioxidant, anti-inflammation, and antiviral, [27] antihypertensive and anticancer, [28] and anti-diabetic activity. [29] Hesperidin has been stated to display numerous pharmacological functions, such as antioxidant, [30] antihyperlipidemic, antidiabetic, antihypertensive and apoptosis. [31] Astragalin (kaempferol 3-glucoside), one of the naturally occurring flavonoids, has been well-known for its diverse pharmacological applications, including neuroprotective, cardioprotective, anti-inflammatory, antiobesity, antiosteoporotic, antiulcer, antioxidant, anti- cancer and antidiabetic properties.…”

Section: Analysis Of Phenolic Compounds By Lc-ms/msmentioning

confidence: 99%

A Biochemical Approach for Hedysarum candidissimum from Turkey: Screening Phytochemicals, Evaluation of Biological Activites, and Molecular Docking Study

Altay

Yeniçeri

Taslimi

et al. 2022

Chemistry & Biodiversity

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This study was designed to screen the phytochemical composition and investigate the biological activities of Hedysarum candidissimum extracts and also support the results with molecular docking studies. LC/MS/MS analysis revealed the presence of 22 phytochemical constituents (mainly phenolic acids, flavonoids, and flavonoid glycosides) in the plant structure. The methanol extract exhibited the strongest antioxidant activity among all the extracts with its strong DPPH radical scavenging and iron reducing capacity, as well as high phenolic and flavonoid contents. Additionally, it was found to be the most promising acetylcholinesterase (AChE: IC 50 : 93.26 μg/mL) and α-glycosidase (AG: IC 50 : 28.57 μg/mL) inhibitory activities, supported by the major phenolics of the species through in silico studies. Ethyl acetate extract had the strongest cytotoxic effect on HT-29 (IC 50 : 63.03 μg/mL) and MDA-MB-453 (IC 50 : 95.36 μg/mL) cancer cell lines. Both extracts exhibited considerable apoptotic and anti-migrative effects on HT-29 cells. The investigations provide phyto-analytical and biopharmacological results which can be extended by in vivo studies in the future.

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“…The caspase-independent mitochondrial-mediated apoptosis was found to be linked to the increase of AIF and Endo G protein expressions. Besides, the anti-proliferative activity was determined to be associated with the downregulation of the PI3K/Akt/mTOR signaling pathway [117]. In a mechanistic study using in vitro (A549 cells) and in silico assays, the flavonoid myricetin (73 µg/mL) showed the capacity to induce anticancer properties against lung cancer cells by promoting cell cycle arrest and ROS-reliant mitochondria-facilitated apoptosis [118].…”

Section: Cancermentioning

confidence: 99%

Protective Effects of Flavonoids Against Mitochondriopathies and Associated Pathologies: Focus on the Predictive Approach and Personalized Prevention

Koklesová

Líšková

Samec

et al. 2021

IJMS

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Multi-factorial mitochondrial damage exhibits a “vicious circle” that leads to a progression of mitochondrial dysfunction and multi-organ adverse effects. Mitochondrial impairments (mitochondriopathies) are associated with severe pathologies including but not restricted to cancers, cardiovascular diseases, and neurodegeneration. However, the type and level of cascading pathologies are highly individual. Consequently, patient stratification, risk assessment, and mitigating measures are instrumental for cost-effective individualized protection. Therefore, the paradigm shift from reactive to predictive, preventive, and personalized medicine (3PM) is unavoidable in advanced healthcare. Flavonoids demonstrate evident antioxidant and scavenging activity are of great therapeutic utility against mitochondrial damage and cascading pathologies. In the context of 3PM, this review focuses on preclinical and clinical research data evaluating the efficacy of flavonoids as a potent protector against mitochondriopathies and associated pathologies.

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The Flavonol Isoquercitrin Promotes Mitochondrial-Dependent Apoptosis in SK-Mel-2 Melanoma Cell via the PI3K/AKT/mTOR Pathway

Cited by 27 publications

References 29 publications

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds

A Biochemical Approach for Hedysarum candidissimum from Turkey: Screening Phytochemicals, Evaluation of Biological Activites, and Molecular Docking Study

Protective Effects of Flavonoids Against Mitochondriopathies and Associated Pathologies: Focus on the Predictive Approach and Personalized Prevention

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