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1.
Rev Fac Cien Med Univ Nac Cordoba ; 77(2): 117-125, 2020 06 16.
Artigo em Espanhol | MEDLINE | ID: mdl-32558516

RESUMO

Introduction: The NAD+dependent proteins deacetylases are called Sirtuins (SIRT). Objectives: Objectives: this review is to study the sirtuins involved in cancer, as well as SIRT1 inhibition studies in patients with coronavirus disease COVID-19. Data source and selection: For this, a search was made in Medline, Scopus and WOS, where descriptive studies of each of the functions of sirtuins were included, adjusted to recent scientific research. SIRT1 inhibition reduces CD8 T cell cytotoxicity in patients with systemic erythematosus lupus, being susceptible to SARS Cov-2 infections. SIRT2 is regulated by the secretion of IL-4 by eosinophils and the increase in SIRT2 increases hyperplasia, in contrast, SIRT3 promotes angiogenesis, inducing cardiac remodeling. SIRT4 is a tumor suppressor, in contrastto SIRT5 that promotes cell proliferation causing colorectal cancer; SIRT6 attenuates herpes virus associated with Kaposi's Sarcoma (KSHV) in immune compromised patients. Suppression of SIRT7 inhibits the growth of endometrial cancer cells. Conclusions: It is concluded that SIRT1, SIRT2 and SIRT4 are involved in the development of cancer, the suppression of SIRT5 and SIRT7 promotes the apoptosis of cancer cells and SIRT6 attenuates the replication of KSHV, in addition to the molecular pathology pathway of COVID-19 is associated with the inhibition of SIRT1 activity that may be related to inflammatory processes.


Assuntos
Betacoronavirus , Infecções por Coronavirus/metabolismo , Neoplasias/metabolismo , Pneumonia Viral/metabolismo , Sirtuína 1/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Histona Desacetilases/metabolismo , Humanos , Imuno-Histoquímica , Pandemias
2.
Anticancer Res ; 40(6): 3155-3161, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487610

RESUMO

BACKGROUND/AIM: The deacetylase sirtuin1 (SIRT1) inhibits tumor suppressor p53 and may promote tumorigenesis; however, SIRT1 effects on leukemia cells are controversial. The aim of this study was to clarify the activity of SIRT1 in leukemia cells. MATERIALS AND METHODS: The effects of SIRT1 inhibition or activation and SIRT1 knockdown or overexpression were examined in two T cell acute lymphoblastic leukemia (T-ALL) cell lines carrying NOTCH1 mutations and three acute myeloid leukemia (AML) cell lines. RESULTS: The growth of T-ALL cells was promoted by SIRT1 inhibition and SIRT1 knockdown but was reduced by SIRT1 activation and overexpression; however, no effects were observed in AML cells. SIRT1 activation decreased NOTCH, NF-κB, and mTOR signaling and inhibited p53, suggesting that the possible mechanisms of T-ALL growth suppression by SIRT1 are independent of p53. CONCLUSION: SIRT1 activators acting through the down-regulation of NOTCH, NF-κB, and mTOR pathways can be novel targeted drugs for NOTCH1-mutated T-ALLs.


Assuntos
NF-kappa B/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores Notch/metabolismo , Sirtuína 1/metabolismo , Carbazóis/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/biossíntese , Sirtuína 1/genética , Serina-Treonina Quinases TOR/metabolismo , Transfecção
3.
Biol Res ; 53(1): 18, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32349783

RESUMO

BACKGROUND: Cisplatin resistance (DDP-resistance) remains one of the major causes of poor prognosis in females with ovarian cancer. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of cellular processes, including chemoresistance. The aim of this study was to explore the role of HOX transcript antisense RNA (HOTAIR) in DDP-resistant ovarian cancer cells. METHODS: DDP-resistant ovarian cancer cell lines (SKOV3/DDP and A2780/DDP) were established. Real-time PCR, western blot, dual-luciferase reporter assay, and flow cytometry were then used to evaluate the effect of HOTAIR/miR-138-5p axis on chemoresistance of DDP-resistant ovarian cancer cells to DDP. RESULTS: We found that HOTAIR was upregulated in DDP-resistant cells, while miR-138-5p was downregulated. Knockdown of HOTAIR increased the expression of miR-138-5p in DDP-resistant cells and miR-138-5p is directly bound to HOTAIR. Upregulation of miR-138-5p induced by HOTAIR siRNA or by its mimics enhanced the chemosensitivity of DDP-resistant cells and decreased the expression of EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) and SIRT1 (sirtuin 1). Furthermore, the HOTAIR silencing-induced chemosensitivity of DDP-resistant cells was weakened by miR-138-5p inhibitor. CONCLUSIONS: These data demonstrate that HOTAIR acts as a sponge of miR-138-5p to prevent its binding to EZH2 and SIRT1, thereby promoting DDP-resistance of ovarian cancer cells. Our work will shed light on the development of therapeutic strategies for ovarian cancer treatment.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Ovarianas/genética , RNA Longo não Codificante/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes/métodos , Humanos , MicroRNAs/antagonistas & inibidores , Reação em Cadeia da Polimerase em Tempo Real , Sirtuína 1/antagonistas & inibidores , Regulação para Cima
4.
J Neurosci ; 40(11): 2332-2342, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32005763

RESUMO

Emotional disorders are common comorbid conditions that further exacerbate the severity and chronicity of chronic pain. However, individuals show considerable vulnerability to the development of chronic pain under similar pain conditions. In this study on male rat and mouse models of chronic neuropathic pain, we identify the histone deacetylase Sirtuin 1 (SIRT1) in central amygdala as a key epigenetic regulator that controls the development of comorbid emotional disorders underlying the individual vulnerability to chronic pain. We found that animals that were vulnerable to developing behaviors of anxiety and depression under the pain condition displayed reduced SIRT1 protein levels in central amygdala, but not those animals resistant to the emotional disorders. Viral overexpression of local SIRT1 reversed this vulnerability, but viral knockdown of local SIRT1 mimicked the pain effect, eliciting the pain vulnerability in pain-free animals. The SIRT1 action was associated with CaMKIIα downregulation and deacetylation of histone H3 lysine 9 at the CaMKIIα promoter. These results suggest that, by transcriptional repression of CaMKIIα in central amygdala, SIRT1 functions to guard against the emotional pain vulnerability under chronic pain conditions. This study indicates that SIRT1 may serve as a potential therapeutic molecule for individualized treatment of chronic pain with vulnerable emotional disorders.SIGNIFICANCE STATEMENT Chronic pain is a prevalent neurological disease with no effective treatment at present. Pain patients display considerably variable vulnerability to developing chronic pain, indicating individual-based molecular mechanisms underlying the pain vulnerability, which is hardly addressed in current preclinical research. In this study, we have identified the histone deacetylase Sirtuin 1 (SIRT1) as a key regulator that controls this pain vulnerability. This study reveals that the SIRT1-CaMKIIaα pathway in central amygdala acts as an epigenetic mechanism that guards against the development of comorbid emotional disorders under chronic pain, and that its dysfunction causes increased vulnerability to the development of chronic pain. These findings suggest that SIRT1 activators may be used in a novel therapeutic approach for individual-based treatment of chronic pain.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Núcleo Central da Amígdala/fisiopatologia , Dor Crônica/fisiopatologia , Angústia Psicológica , Sirtuína 1/fisiologia , Neuralgia do Trigêmeo/fisiopatologia , Acetilação , Animais , Ansiedade/etiologia , Ansiedade/fisiopatologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Núcleo Central da Amígdala/enzimologia , Dor Crônica/psicologia , Depressão/etiologia , Depressão/fisiopatologia , Suscetibilidade a Doenças , Regulação para Baixo , Comportamento Exploratório , Neurônios GABAérgicos/enzimologia , Vetores Genéticos , Histonas/metabolismo , Hiperalgesia/fisiopatologia , Masculino , Camundongos , Regiões Promotoras Genéticas , Ratos , Ratos Wistar , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Natação , Transcrição Genética , Neuralgia do Trigêmeo/psicologia
5.
Metabolism ; 104: 154143, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31927009

RESUMO

Insulin deficiency in type 2 diabetes mellitus (DM) involves a decline in both pancreatic ß-cell mass and function. Enhancing ß-cell preservation represents an important therapeutic strategy to treat type 2 DM. Far-infrared (FIR) radiation has been found to induce promyelocytic leukemia zinc finger protein (PLZF) activation to protect the vascular endothelium in diabetic mice. The influence of FIR on ß-cell preservation is unknown. Our previous study reveals that the biologically effective wavelength of FIR is 8-10 µm. In the present study, we investigated the biological effects of FIR (8-10 µm) on both survival and insulin secretion function of ß-cells. FIR reduced pancreatic islets loss and increased insulin secretion in nicotinamide-streptozotocin-induced DM mice, but only promoted insulin secretion in DM PLZF-/- mice. FIR-upregulated PLZF to induce an anti-apoptotic effect in a ß cell line RIN-m5f. FIR also upregulated mitochondrial function and the ratio of NAD+/NADH, and then induced Sirtuin1 (Sirt1) expression. The mitochondria Complex I inhibitor rotenone blocked FIR-induced PLZF and Sirt1. The Sirt1 inhibitor EX527 and Sirt1 siRNA inhibited FIR-induced PLZF and insulin respectively. Sirt1 upregulation also increased CaV1.2 expression and calcium influx that promotes insulin secretion in ß-cells. In summary, FIR-enhanced mitochondrial function prevents ß-cell apoptosis and enhances insulin secretion in DM mice through the Sirt1 pathway.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/radioterapia , Raios Infravermelhos , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/efeitos da radiação , Sirtuína 1/metabolismo , Sirtuína 1/efeitos da radiação , Animais , Apoptose/genética , Apoptose/efeitos da radiação , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo L/efeitos da radiação , Teste de Tolerância a Glucose , Secreção de Insulina/efeitos da radiação , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Niacinamida , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Sirtuína 1/antagonistas & inibidores , Análise de Sobrevida , Regulação para Cima
6.
Anticancer Drugs ; 31(1): 19-26, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31490284

RESUMO

Sirtuin-1 (Sirt-1), an NAD-dependent deacetylase, promotes tumorigenesis in glioma; however, whether the Sirt-1 specific inhibitor, EX527 exerts antitumor effects and the underlying mechanism in glioma requires further investigation. In the present study, the proliferative and colony formation abilities of two glioma cell lines (U87MG and LN-299) were inhibited by EX527. Treatment with EX527 increased the number of apoptotic cells (Annexin V-fluorescein isothiocyanate/propidium iodide); pretreatment with the caspase inhibitor Z-VAD-FMK suppressed EX527-induced apoptosis, suggesting that EX527 induced caspase-dependent apoptosis. In addition, western blotting revealed that EX527 treatment increased the expression of cleaved-caspase-3, poly (ADP-ribose) polymerase-1, B-cell lymphoma 2 (Bcl-2)-associated-X-protein and Bcl-2-like 11 but decreased that of Bcl-2. p53 is deacetylated by Sirt-1, attenuating its function. Furthermore, EX527 upregulated the expression of p53, acetylated p53 and the p53 target gene p21. This result suggests that EX527 induced cell apoptosis by activating p53 in glioma. Of note, EX527 exhibited antitumor effects on patient-derived glioma cells under three-dimensional culture conditions. Collectively, the results of the present study indicated that EX527 may be used as an effective compound in the treatment of glioma.


Assuntos
Carbazóis/farmacologia , Glioma/tratamento farmacológico , Sirtuína 1/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Clorometilcetonas de Aminoácidos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Inibidores de Caspase/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glioma/metabolismo , Glioma/patologia , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
7.
J Surg Res ; 245: 441-452, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445496

RESUMO

BACKGROUND: Whitmania pigra Whitman (W pigra), a traditional Chinese medicine, has functions of breaking stagnant and eliminating blood stasis. The aim of this study was to investigate the underlying mechanism of W pigra against deep vein thrombosis (DVT). METHODS: A rat model of DVT induced by inferior vena cava stenosis was successfully established. Rats were administered vehicle (saline solution, p.o.), three doses of W pigra aqueous extract (34.7, 104.2, or 312.5 mg crude W pigra/kg, p.o.), heparin (200 U/kg, i.v.), or clopidogrel (25 mg/kg, p.o.) once daily for 2 d. Thrombus weight and histopathological changes were examined. Blood samples were collected to determine blood cell counts, blood viscosity, blood coagulation, blood fibrinolysis, serum levels of interleukin-1ß, and tumor necrosis factor-α. Protein expressions of Sirtuin1 (SIRT1), acetylated p65 (Ace-p65), and phosphorylated p65 (p-p65) were determined by Western blot. Furthermore, SIRT1-specific inhibitor EX527 was applied to confirm the role of SIRT1 in the antithrombotic effect of W pigra. RESULTS: W pigra significantly decreased thrombus weight. W pigra had no effects on blood cell counts, whole blood viscosity, blood coagulation, blood fibrinolysis. However, it reduced tissue factor protein expression in the vein wall and thrombus. Moreover, it sharply increased SIRT1 protein expression and decreased leukocytes recruitment in the thrombus and vein wall, serum levels of interleukin-1ß and tumor necrosis factor-α, and protein expressions of Ace-p65 and p-p65. Furthermore, the antithrombotic effect of W pigra was significantly abolished by EX527. CONCLUSIONS: Aqueous extract of W pigra effectively reduced DVT burden by inhibiting inflammation via SIRT1/nuclear factor-kappa B signaling pathway.


Assuntos
Produtos Biológicos/uso terapêutico , Sanguessugas , NF-kappa B/metabolismo , Sirtuína 1/metabolismo , Trombose Venosa/tratamento farmacológico , Animais , Produtos Biológicos/farmacologia , Carbazóis , Citocinas/sangue , Avaliação Pré-Clínica de Medicamentos , Feminino , Inflamação/tratamento farmacológico , Masculino , Medicina Tradicional Chinesa , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Tromboplastina/metabolismo , Trombose Venosa/metabolismo
8.
Pharm Biol ; 58(1): 16-24, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31854225

RESUMO

Context: XingNaoJing injection (XNJ), extracted from a traditional compound Chinese medicine Angong niuhuang pill, is well known for treating stroke in the clinic, but the specific effects and mechanisms remain unclear.Objective: We investigated the mechanistic basis for the protective effect of XNJ on cerebral ischaemia/reperfusion (I/R) injury.Materials and methods: Five groups of 10 SD rats underwent 2 h of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. XNJ at 10 and 15 mL/kg was intraperitoneally administered 24 h before ischaemia and at the onset of reperfusion respectively. The silent information regulator 1 (SIRT1) inhibitor EX527 was intracerebroventricularly injected 0.5 h before reperfusion. Cerebral infarction size, neurological scores, morphological changes, and expression levels of inflammatory mediators and SIRT1 were measured. Furthermore, human brain microvascular endothelial cells (HBMECs) were subjected to 3 h oxygen and glucose deprivation (OGD) followed by 24 h reoxygenation to mimic cerebral I/R in vitro. EX527 pre-treatment occurred 1 h before OGD. SIRT1 and inflammatory mediator levels were analyzed.Results: Both XNJ doses significantly decreased cerebral infarct area (40.11% vs. 19.66% and 9.87%) and improved neurological scores and morphological changes. Inflammatory mediator levels were remarkably decreased in both model systems after XNJ treatment. XNJ also enhanced SIRT1 expression. Notably, the SIRT1 inhibitor EX527 attenuated the XNJ-mediated decrease in inflammation in vivo and in vitro.Conclusions: XNJ improved cerebral I/R injury through inhibiting the inflammatory response via the SIRT1 pathway, which may be a useful target in treating cerebral I/R injury.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Encéfalo/citologia , Isquemia Encefálica/tratamento farmacológico , Carbazóis/farmacologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Humanos , Infarto da Artéria Cerebral Média , Inflamação/patologia , Masculino , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo
9.
Phytomedicine ; 66: 153112, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786318

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) spreads further with continuance and increasing incidence due to its high-grade malignancy and metastasis. More effectual strategies on blocking proliferation and metastasis of cancer cells should be studied in HCC. Dulcitol, a natural product extracted from euonymus alatus, was reported that it could induce apoptosis of C6 glioma cells. However, the underlying mechanism of Dulcitol on HCC remains unclea. PURPOSE: In this study, we aimed to reveal the effect and potential mechanisms of Dulcitol on hepatocellular carcinoma in vitro and in vivo. Study design and methods The cell proliferation and apoptosis were evaluated by MTT, Ki-67 and Hoechst 33258/PI double staining. The migratory and invasive abilities of HepG2 cells were measured by wound-healing and transwell assays. Pathological changes of tumor tissue were observed by HE staining and IHC methods. The expression levels of protein were detected using Western Blot analysis. RESULTS: The results showed that Dulcitol inhibited HepG2 cells proliferation by down-regulating the protein expression of SIRT1, Bcl-2, along with up-regulating p53, acetylated-p53 (K382), cleaved-caspase9, cleaved-caspase3, Bax, and cytochrome c in a dose-dependent manner. Furthermore, Dulcitol surpressed the migration and invasion of HepG2 cells through decreasing the levels of MMP-2, uPA and MMP-9 and increasing E-cadherin associated with tumor invasion. In vivo, Dulcitol distinctly inhibited the growth of HepG2 cancer xenograft tumors via inhibiting SIRT1/p53 pathway. CONCLUSIONS: Our findings suggested that Dulcitol acted as a SIRT1 inhibitor, inducing apoptosis and inhibiting proliferation, migration and invasion of HepG2 cells and its modulatory mechanism seemed to be associated with regulation of MMPs, SIRT1/p53 pathways.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Galactitol/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Sirtuína 1/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Células Hep G2 , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima
10.
Stem Cell Res Ther ; 10(1): 393, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847890

RESUMO

AIM: Myocardial infarction (MI) is a severe disease with increased mortality and disability rates, posing heavy economic burden for society. Exosomes were uncovered to mediate intercellular communication after MI. This study aims to explore the effect and mechanism of lncRNA KLF3-AS1 in exosomes secreted by human mesenchymal stem cells (hMSCs) on pyroptosis of cardiomyocytes and MI. METHODS: Exosomes from hMSCs were isolated and identified. Exosomes from hMSCs with transfection of KLF3-AS1 for overexpression were injected into MI rat model or incubated with hypoxia cardiomyocytes. Effect of KLF3-AS1 on MI area, cell viability, apoptosis, and pyroptosis was determined. The relationship among miR-138-5p, KLF3-AS1, and Sirt1 was verified by dual-luciferase reporter assay. Normal cardiomyocytes were transfected with miR-138-5p inhibitor or sh-Sirt1 to clarify whether alteration of miR-138-5p or sh-Sirt1 can regulate the effect of KLF3-AS1 on cardiomyocytes. RESULTS: Exosomes from hMSCs were successfully extracted. Transfection of KLF3-AS1 exosome in rats and incubation with KLF3-AS1 exosome in hypoxia cardiomyocytes both verified that overexpression of KLF3-AS1 in exosomes leads to reduced MI area, decreased cell apoptosis and pyroptosis, and attenuated MI progression. KLF3-AS1 can sponge miR-138-5p to regulate Sirt1 expression. miR-138-5p inhibitor transfection and KLF3-AS1 exosome incubation contribute to attenuated pyroptosis and MI both in vivo and in vitro, while transfection of sh-Sirt1 could reverse the protective effect of exosomal KLF3-AS1 on hypoxia cardiomyocytes. CONCLUSION: LncRNA KLF3-AS1 in exosomes secreted from hMSCs by acting as a ceRNA to sponge miR-138-5p can regulate Sirt1 so as to inhibit cell pyroptosis and attenuate MI progression.


Assuntos
Exossomos/metabolismo , MicroRNAs/metabolismo , Piroptose , RNA Longo não Codificante/metabolismo , Sirtuína 1/metabolismo , Animais , Antagomirs/metabolismo , Apoptose , Hipóxia Celular , Meios de Cultivo Condicionados/farmacologia , Exossomos/transplante , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Piroptose/efeitos dos fármacos , Interferência de RNA , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Ratos , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Regulação para Cima
11.
Int J Mol Sci ; 20(22)2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31726691

RESUMO

Sirtuins, a family of nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylases, are promising targets for anticancer treatment. Recently, we characterized a novel pan-sirtuin (SIRT) inhibitor, MC2494, displaying antiproliferative effects and able to induce death pathways in several human cancer cell lines and decrease tumor growth in vivo. Based on the chemical scaffold of MC2494, and by applying a structure-activity relationship approach, we developed a small library of derivative compounds and extensively analyzed their enzymatic action at cellular level as well as their ability to induce cell death. We also investigated the effect of MC2494 on regulation of cell cycle progression in different cancer cell lines. Our investigations indicated that chemical substitutions applied to MC2494 scaffold did not confer higher efficacy in terms of biological activity and SIRT1 inhibition, but carbethoxy-containing derivatives showed higher SIRT2 specificity. The carbethoxy derivative of MC2494 and its 2-methyl analog displayed the strongest enzymatic activity. Applied chemical modifications improved the enzymatic selectivity of these SIRT inhibitors. Additionally, the observed activity of MC2494 via cell cycle and apoptotic regulation and inhibition of cell migration supports the potential role of SIRTs as targets in tumorigenesis and makes SIRT-targeting molecules good candidates for novel pharmacological approaches in personalized medicine.


Assuntos
Antineoplásicos , Inibidores de Histona Desacetilases , Proteínas de Neoplasias , Neoplasias , Sirtuína 1 , Sirtuína 2 , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Células HL-60 , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Células K562 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Molibdoferredoxina , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo , Sirtuína 2/antagonistas & inibidores , Sirtuína 2/metabolismo , Células U937
12.
World J Gastroenterol ; 25(38): 5800-5813, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31636473

RESUMO

BACKGROUND: Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase that is involved in various diseases, including cancers, metabolic diseases, and inflammation-associated diseases. However, the role of SIRT1 in ulcerative colitis (UC) is still confusing. AIM: To investigate the role of SIRT1 in intestinal epithelial cells (IECs) in UC and further explore the underlying mechanisms. METHODS: We developed a coculture model using macrophages and Caco-2 cells. After treatment with the SIRT1 activator SRT1720 or inhibitor nicotinamide (NAM), the expression of occludin and zona occludens 1 (ZO-1) was assessed by Western blot analysis. Annexin V-APC/7-AAD assays were performed to evaluate Caco-2 apoptosis. Dextran sodium sulfate (DSS)-induced colitis mice were exposed to SRT1720 or NAM for 7 d. Transferase-mediated dUTP nick-end labeling (TUNEL) assays were conducted to assess apoptosis in colon tissues. The expression levels of glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, caspase-9, and caspase-3 in Caco-2 cells and the colon tissues of treated mice were examined by quantitative real-time PCR and Western blot. RESULTS: SRT1720 treatment increased the protein levels of occludin and ZO-1 and inhibited Caco-2 apoptosis, whereas NAM administration caused the opposite effects. DSS-induced colitis mice treated with SRT1720 had a lower disease activity index (P < 0.01), histological score (P < 0.001), inflammatory cytokine levels (P < 0.01), and apoptotic cell rate (P < 0.01), while exposure to NAM caused the opposite effects. Moreover, SIRT1 activation reduced the expression levels of GRP78, CHOP, cleaved caspase-12, cleaved caspase-9, and cleaved caspase-3 in Caco-2 cells and the colon tissues of treated mice. CONCLUSION: SIRT1 activation reduces apoptosis of IECs via the suppression of endoplasmic reticulum stress-mediated apoptosis-associated molecules CHOP and caspase-12. SIRT1 activation may be a potential therapeutic strategy for UC.


Assuntos
Apoptose , Colite Ulcerativa/patologia , Estresse do Retículo Endoplasmático , Mucosa Intestinal/patologia , Sirtuína 1/metabolismo , Animais , Células CACO-2 , Caspase 12/metabolismo , Técnicas de Cocultura , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Mucosa Intestinal/citologia , Macrófagos , Camundongos , Niacinamida/administração & dosagem , Sirtuína 1/antagonistas & inibidores , Fator de Transcrição CHOP/metabolismo
13.
World J Gastroenterol ; 25(36): 5434-5450, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31576091

RESUMO

BACKGROUND: High mobility group box-1 (HMGB1), recognized as a representative of damage-associated molecular patterns, is released during cell injury/death, triggering the inflammatory response and ultimately resulting in tissue damage. Dozens of studies have shown that HMGB1 is involved in certain diseases, but the details on how injured hepatocytes release HMGB1 need to be elicited. AIM: To reveal HMGB1 release mechanism in hepatocytes undergoing oxidative stress. METHODS: C57BL6/J male mice were fed a high-fat diet for 12 wk plus a single binge of ethanol to induce severe steatohepatitis. Hepatocytes treated with H2O2 were used to establish an in vitro model. Serum alanine aminotransferase, liver H2O2 content and catalase activity, lactate dehydrogenase and 8-hydroxy-2-deoxyguanosine content, nicotinamide adenine dinucleotide (NAD+) levels, and Sirtuin 1 (Sirt1) activity were detected by spectrophotometry. HMGB1 release was measured by enzyme linked immunosorbent assay. HMGB1 translocation was observed by immunohistochemistry/immunofluorescence or Western blot. Relative mRNA levels were assayed by qPCR and protein expression was detected by Western blot. Acetylated HMGB1 and poly(ADP-ribose)polymerase 1 (Parp1) were analyzed by Immunoprecipitation. RESULTS: When hepatocytes were damaged, HMGB1 translocated from the nucleus to the cytoplasm because of its hyperacetylation and was passively released outside both in vivo and in vitro. After treatment with Sirt1-siRNA or Sirt1 inhibitor (EX527), the hyperacetylated HMGB1 in hepatocytes increased, and Sirt1 activity inhibited by H2O2 could be reversed by Parp1 inhibitor (DIQ). Parp1 and Sirt1 are two NAD+-dependent enzymes which play major roles in the decision of a cell to live or die in the context of stress . We showed that NAD+ depletion attributed to Parp1 activation after DNA damage was caused by oxidative stress in hepatocytes and resulted in Sirt1 activity inhibition. On the contrary, Sirt1 suppressed Parp1 by negatively regulating its gene expression and deacetylation. CONCLUSION: The functional inhibition between Parp1 and Sirt1 leads to HMGB1 hyperacetylation, which leads to its translocation from the nucleus to the cytoplasm and finally outside the cell.


Assuntos
Fígado Gorduroso/patologia , Proteína HMGB1/metabolismo , Hepatócitos/patologia , Fígado/patologia , Sirtuína 1/metabolismo , Acetilação/efeitos dos fármacos , Animais , Carbazóis/farmacologia , Linhagem Celular , Núcleo Celular/metabolismo , Células Cultivadas , Citoplasma/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Etanol/toxicidade , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/etiologia , Hepatócitos/citologia , Humanos , Peróxido de Hidrogênio/toxicidade , Fígado/citologia , Fígado/efeitos dos fármacos , Testes de Função Hepática , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Compostos de Quinolínio/farmacologia , RNA Interferente Pequeno/metabolismo , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética
14.
Neoplasia ; 21(10): 974-988, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31442917

RESUMO

We recently described a positive feedback loop connecting c-MYC, NAMPT, DBC1 and SIRT1 that contributes to unrestricted cancer cell proliferation. Here we determine the relevance of the loop for serrated route intestinal tumorigenesis using genetically well-defined BrafV600E and K-rasG12D mouse models. In both models we show that c-MYC and SIRT1 protein expression increased through progression from hyperplasia to invasive carcinomas and metastases. It correlated with high NAMPT expression and was directly associated to activation of the oncogenic drivers. Assessing functional and molecular consequences of pharmacological interference with factors of the loop, we found that inhibition of NAMPT resulted in apoptosis and reduced clonogenic growth in human BRAF-mutant colorectal cancer cell lines and patient-derived tumoroids. Blocking SIRT1 activity was only effective when combined with a PI3K inhibitor, whereas the latter antagonized the effects of NAMPT inhibition. Interfering with the positive feedback loop was associated with down-regulation of c-MYC and temporary de-repression of TP53, explaining the anti-proliferative and pro-apoptotic effects. In conclusion we show that the c-MYC-NAMPT-DBC1-SIRT1 positive feedback loop contributes to murine serrated tumor progression. Targeting the feedback loop exerted a unique, dual therapeutic effect of oncoprotein inhibition and tumor suppressor activation. It may therefore represent a promissing target for serrated colorectal cancer, and presumably for other cancer types with deregulated c-MYC.


Assuntos
Transformação Celular Neoplásica , Citocinas/metabolismo , Neoplasias Intestinais/etiologia , Neoplasias Intestinais/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Oncogenes , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sirtuína 1/metabolismo , Animais , Apoptose/genética , Biomarcadores , Biópsia , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Imuno-Histoquímica , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/patologia , Camundongos , Mutação , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais , Sirtuína 1/antagonistas & inibidores
15.
ACS Chem Biol ; 14(8): 1802-1810, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31373792

RESUMO

Small molecule inhibitors for SIRT2, a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent protein lysine deacylases, have shown promise in treating cancer and neurodegenerative diseases. Developing SIRT2-selective inhibitors with better pharmacological properties is key to further realize the therapeutic potential of targeting SIRT2. One of the best SIRT2-selective inhibitors reported is a thiomyristoyl lysine compound called TM, which showed promising anticancer activity in mouse models without much toxicity to normal cells. The main limitations of TM, however, are the low aqueous solubility and lack of X-ray crystal structures to aid future drug design. Here, we designed and synthesized a glucose-conjugated TM (glucose-TM) analog with superior aqueous solubility. Although glucose-TM is not cell permeable, the excellent aqueous solubility allowed us to obtain a crystal structure of SIRT2 in complex with it. The structure enabled us to design several new TM analogs, one of which, NH4-6, showed superior water solubility and better anticancer activity in cell culture. The results of these studies provided important insights that will further fuel the future development of improved SIRT2 inhibitors as promising therapeutics for treating cancer and neurodegeneration.


Assuntos
Glucosídeos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Lipopeptídeos/farmacologia , Sirtuína 2/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Glucosídeos/síntese química , Glucosídeos/química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Lipopeptídeos/síntese química , Lipopeptídeos/química , Estrutura Molecular , Sirtuína 1/antagonistas & inibidores , Sirtuína 2/química , Solubilidade
16.
Int J Biol Macromol ; 140: 454-468, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31404596

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive disease exemplified by a poor prognosis, greater degrees of relapse, the absence of hormonal receptors for coherent utilization of targeted therapy, poor response to currently available therapeutics and development of chemoresistance. Aberrant activity of sirtuins (SIRTs) has strong implications in the metastatic and oncogenic progression of TNBC. Synthetic SIRT inhibitors are effective, however, they have shown adverse side effects emphasizing the need for plant-derived inhibitors (PDIs). In the current study, we identified potential plant-derived sirtuin inhibitors using in silico approach i.e. molecular docking, ADMET and molecular dynamics simulations (MD). Docking studies revealed that Sulforaphane, Kaempferol and Apigenin exhibits the highest docking scores against SIRT1 & 5, 3 and 6 respectively. ADMET analysis of above hits demonstrated drug-like profile. MD of prioritized SIRTs-PDIs complexes displayed stability with insignificant deviations throughout the trajectory. Furthermore, we determined the effect of our prioritized molecules on cellular viability, global activity as well as protein expression of sirtuins and stemness of TNBC cells utilizing in vitro techniques. Our in vitro findings complements our in silico results. Collectively, these findings provide a better insight into the structural basis of sirtuin inhibition and can facilitate drug design process for TNBC management.


Assuntos
Apigenina/química , Isotiocianatos/química , Quempferóis/química , Sirtuínas/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Apigenina/isolamento & purificação , Linhagem Celular Tumoral , Simulação por Computador , Feminino , Humanos , Isotiocianatos/isolamento & purificação , Quempferóis/isolamento & purificação , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Plantas/química , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/química , Sirtuína 3/antagonistas & inibidores , Sirtuína 3/química , Sirtuínas/antagonistas & inibidores , Sirtuínas/química , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
17.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340436

RESUMO

Status epilepticus may decrease mitochondrial biogenesis, resulting in neuronal cell death occurring in the hippocampus. Sirtuin 1 (SIRT1) functionally interacts with peroxisome proliferator-activated receptors and γ coactivator 1α (PGC-1α), which play a crucial role in the regulation of mitochondrial biogenesis. In Sprague-Dawley rats, kainic acid was microinjected unilaterally into the hippocampal CA3 subfield to induce bilateral seizure activity. SIRT1, PGC-1α, and other key proteins involving mitochondrial biogenesis and the amount of mitochondrial DNA were investigated. SIRT1 antisense oligodeoxynucleotide was used to evaluate the relationship between SIRT1 and mitochondrial biogenesis, as well as the mitochondrial function, oxidative stress, and neuronal cell survival. Increased SIRT1, PGC-1α, and mitochondrial biogenesis machinery were found in the hippocampus following experimental status epilepticus. Downregulation of SIRT1 decreased PGC-1α expression and mitochondrial biogenesis machinery, increased Complex I dysfunction, augmented the level of oxidized proteins, raised activated caspase-3 expression, and promoted neuronal cell damage in the hippocampus. The results suggest that the SIRT1 signaling pathway may play a pivotal role in mitochondrial biogenesis, and could be considered an endogenous neuroprotective mechanism counteracting seizure-induced neuronal cell damage following status epilepticus.


Assuntos
Região CA3 Hipocampal/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Sirtuína 1/genética , Estado Epiléptico/genética , Animais , Região CA3 Hipocampal/metabolismo , Região CA3 Hipocampal/patologia , Caspase 3/genética , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Injeções Intraventriculares , Ácido Caínico/administração & dosagem , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Biogênese de Organelas , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia , Técnicas Estereotáxicas
18.
Oxid Med Cell Longev ; 2019: 8765954, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281594

RESUMO

This article is directed at highlighting the involvement of the endogenous stress sensor SIRT1 (silent information regulator T1) as a possible factor involved in hepatoprotection. The selective SIRT1 modulators whether activators (STACs) or inhibitors are being tried experimentally and clinically. We discuss the modulation of SIRT1 on cytoprotection or even cytotoxicity in the liver chemically injured by hepatotoxic agents in rats, to shed light on the crosstalk between SIRT1 and its modulators. A combination of D-galactosamine and lipopolysaccharide (D-GalN/LPS) downregulated SIRT1 expression, while SIRT1 activators, SRT1720, resveratrol, and quercetin, upregulated SIRT1 and alleviated D-GalN/LPS-induced acute hepatotoxicity. Liver injury markers exhibited an inverse relationship with SIRT1 expression. However, under subchronic hepatotoxicity, quercetin decreased the significant increase in SIRT1 expression to lower levels which are still higher than normal ones and mitigated the liver-damaging effects of carbon tetrachloride. Each of these STACs was hepatoprotective and returned the conventional antioxidant enzymes to the baseline. Polyphenols tend to fine-tune SIRT1 expression towards normal in the liver of intoxicated rats in both acute and subchronic studies. Together, all these events give an impression that the cytoprotective effects of SIRT1 are exhibited within a definite range of expression. The catalytic activity of SIRT1 is important in the hepatoprotective effects of polyphenols where SIRT1 inhibitors block and the allosteric SIRT1 activators mimic the hepatoprotective effects of polyphenols. Our findings indicate that the pharmacologic modulation of SIRT1 could represent both an important move in alleviating hepatic insults and a future major step in the treatment of xenobiotic-induced hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Humanos , Polifenóis/farmacologia
19.
Eur J Med Chem ; 180: 224-237, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306909

RESUMO

Cytotoxic effects of (R)-4'-methylklavuzon were investigated on hepatocellular carcinoma cells (HuH-7 and HepG2) and HuH-7 EpCAM+/CD133+ cancer stem cells. IC50 of (R)-4'-methylklavuzon was found as 1.25 µM for HuH-7 parental cells while it was found as 2.50 µM for HuH-7 EpCAM+/CD133+ cancer stem cells. (R)-4'-methylklavuzon tended to show more efficient in vitro cytotoxicity with its lower IC50 values on hepatocellular carcinoma cell lines compared to its lead molecule, goniothalamin and FDA-approved drugs, sorafenib and regorafenib. Cell-based Sirtuin/HDAC enzyme activity measurements revealed that endogenous Sirtuin/HDAC enzymes were reduced by 40% compared to control. SIRT1 protein levels were upregulated indicating triggered DNA repair mechanism. p53 was overexpressed in HepG2 cells. (R)-4'-methylklavuzon inhibited CRM1 protein providing increased retention of p53 and RIOK2 protein in the nucleus. HuH-7 parental and EpCAM+/CD133+ cancer stem cell spheroids lost intact morphology. 3D HepG2 spheroid viabilities were decreased in a correlation with upregulation in p53 protein levels.


Assuntos
Antígeno AC133/antagonistas & inibidores , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Molécula de Adesão da Célula Epitelial/antagonistas & inibidores , Carioferinas/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Naftalenos/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Sirtuína 1/antagonistas & inibidores , Antígeno AC133/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Molécula de Adesão da Célula Epitelial/metabolismo , Células Hep G2 , Humanos , Carioferinas/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Sirtuína 1/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
20.
Mol Carcinog ; 58(10): 1876-1885, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292999

RESUMO

Sirtuin-1 and -3 (SIRT1 and SIRT3) are important nicotinamide adenine dinucleotide (NAD+ )-dependent deacetylases known to regulate a variety of cellular functions. Studies have shown that SIRT1 and SIRT3 were overexpressed in human melanoma cells and tissues and their inhibition resulted in a significant antiproliferative response in human melanoma cells and antitumor response in a mouse xenograft model of melanoma. In this study, we determined the antiproliferative efficacy of a newly identified dual small molecule inhibitor of SIRT1 and SIRT3, 4'-bromo-resveratrol (4'-BR), in human melanoma cell lines (G361, SK-MEL-28, and SK-MEL-2). Our data demonstrate that 4'-BR treatment of melanoma cells resulted in (a) decrease in proliferation and clonogenic survival; (b) induction of apoptosis accompanied by a decrease in procaspase-3, procaspase-8, and increase in the cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP); (c) marked downregulation of proliferating cell nuclear antigen (PCNA); and (d) inhibition of melanoma cell migration. Further, 4'-BR caused a G0/G1 phase arrest of melanoma cells that was accompanied by an increase in WAF-1/P21 and decrease in Cyclin D1/Cyclin-dependent kinase 6 protein levels. Furthermore, we found that 4'-BR causes a decrease in lactate production, glucose uptake, and NAD+ /NADH ratio. These responses were accompanied by downregulation in lactate dehydrogenase A and glucose transporter 1 in melanoma cells. Collectively, our data suggest that dual inhibition of SIRT1 and SIRT3 using 4'-BR imparted antiproliferative effects in melanoma cells through a metabolic reprogramming and affecting the cell cycle and apoptosis signaling. Therefore, concomitant pharmacological inhibition of SIRT1 and SIRT3 needs further investigation for melanoma management.


Assuntos
Melanoma/tratamento farmacológico , Resorcinóis/farmacologia , Sirtuína 1/genética , Sirtuína 3/genética , Estilbenos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ácido Láctico/metabolismo , Melanoma/genética , Melanoma/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Sirtuína 1/antagonistas & inibidores , Sirtuína 3/antagonistas & inibidores
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