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1.
Anticancer Res ; 41(9): 4215-4228, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475041

RESUMO

BACKGROUND/AIM: Tyrosine kinase inhibitors (TKIs) are used for the treatment of both wild type and mutant non-small cell lung cancer (NSCLC); however, acquired resistance is a major clinical challenge. Herein, we aimed to investigate the effects of telmisartan (Tel), CFM 4.16 and sorafenib combination in rociletinib resistant NSCLC tumors. MATERIALS AND METHODS: 3D spheroid cultures and western blotting were used for evaluating cytotoxic effects and protein expression. An in vivo rociletinib resistant H1975 xenograft model of NSCLC was developed by subcutaneous injection of rociletinib resistant H1975 cells into nude mice. RESULTS: Tel, CFM 4.16 and sorafenib combination displayed superior anti-cancer effects in 3D spheroid cultures and a rociletinib resistant H1975 xenograft model of NSCLC by decreasing the protein expression of oncogenic and cancer stem cell markers (Nanog, Sox2 and Oct4). CONCLUSION: Tel facilitates effective penetration of CFM 4.16 and sorafenib in rociletinib resistant H1975 models of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Esferoides Celulares/citologia , Compostos de Espiro/administração & dosagem , Telmisartan/administração & dosagem , Tiadiazóis/administração & dosagem , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Esferoides Celulares/efeitos dos fármacos , Compostos de Espiro/farmacologia , Telmisartan/farmacologia , Tiadiazóis/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Anticancer Res ; 41(9): 4321-4331, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475052

RESUMO

BACKGROUND/AIM: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are key drugs in cancer treatment due to their minor adverse effects and outstanding anticancer effects. However, drugs for overcoming EGFR-TKI resistance are not in clinical use so far. Therefore, to overcome resistance, we focused on lurasidone, a new antipsychotic drug, due to its mild adverse effect profile from the viewpoint of drug repositioning. MATERIALS AND METHODS: We explored the effects of lurasidone alone or in combination with EGFR-TKI on the growth of osimertinib-resistant cancer cells the anti-apoptotic marker expression such as survivin, and autophagy levels by LC-3B expression. RESULTS: Within a non-toxic concentration range in normal cells, lurasidone and osimertinib combination therapy showed a growth-inhibitory effect in osimertinib-resistant cancer cells in vitro and in vivo. Furthermore, lurasidone decreased survivin expression and mildly induced autophagy. CONCLUSION: Lurasidone may increase the sensitivity to osimertinib in osimertinib-resistant cancer cells in drug repurposing.


Assuntos
Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Cloridrato de Lurasidona/administração & dosagem , Survivina/metabolismo , Células A549 , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Cloridrato de Lurasidona/farmacologia , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445227

RESUMO

Osimertinib is the latest generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor used for patients with EGFR-mutated non-small cell lung cancer (NSCLC). We aimed to explore the novel mechanisms of osimertinib by particularly focusing on EGFR-independent effects, which have not been well characterized. We explored the EGFR-independent effects of osimertinib on cell proliferation using NSCLC cell lines, an antibody array analysis, and the association between the action of osimertinib and the ephrin receptor B4 (EphB4). We also studied the clinicopathological significance of EphB4 in 84 lung adenocarcinoma patients. Osimertinib exerted significant inhibitory effects on cell growth and cell cycle progression by promoting the phosphorylation of p53 and p21 and decreasing cyclin D1 expression independently of EGFR. EphB4 was significantly suppressed by osimertinib and promoted cell growth and sensitivity to osimertinib. The EphB4 status in carcinoma cells was positively correlated with tumor size, T factor, and Ki-67 labeling index in all patients and was associated with poor relapse-free survival in EGFR mutation-positive patients. EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status.


Assuntos
Acrilamidas/farmacologia , Adenocarcinoma de Pulmão , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas , Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares , Proteínas de Neoplasias/metabolismo , Receptor EphB4/metabolismo , Células A549 , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ciclo Celular/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Mutação , Proteínas de Neoplasias/genética , Receptor EphB4/genética
4.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203300

RESUMO

Pain symptoms in temporomandibular disorders (TMD) predominantly affect reproductive women, suggesting that estrogen regulates pain perception. However, how estrogen contributes to chronic TMD pain remains largely unclear. In the present study, we performed behavioral tests, electrophysiology, Western blot and immunofluorescence to investigate the role and underlying mechanisms of estrogen in dental experimental occlusal interference (EOI)-induced chronic masseter mechanical hyperalgesia in rats. We found that long-term 17ß-estradiol (E2) replacement exacerbated EOI-induced masseter hyperalgesia in a dose-dependent manner in ovariectomized (OVX) rats. Whole-cell patch-clamp recordings demonstrated that E2 (100 nM) treatment enhanced the excitability of isolated trigeminal ganglion (TG) neurons in OVX and OVX EOI rats, and EOI increased the functional expression of transient receptor potential vanilloid-1 (TRPV1). In addition, E2 replacement upregulated the protein expression of TRPV1 in EOI-treated OVX rats. Importantly, intraganglionic administration of the TRPV1 antagonist AMG-9810 strongly attenuated the facilitatory effect of E2 on EOI-induced masseter mechanical sensitivity. These results demonstrate that E2 exacerbated EOI-induced chronic masseter mechanical hyperalgesia by increasing TG neuronal excitability and TRPV1 function. Our study helps to elucidate the E2 actions in chronic myogenic TMD pain and may provide new therapeutic targets for relieving estrogen-sensitive pain.


Assuntos
Hiperalgesia/tratamento farmacológico , Neurônios Aferentes/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Gânglio Trigeminal/metabolismo , Acrilamidas/farmacologia , Animais , Western Blotting , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Estradiol/genética , Estradiol/metabolismo , Feminino , Imunofluorescência , Hiperalgesia/metabolismo , Ovariectomia , Ratos , Ratos Sprague-Dawley , Gânglio Trigeminal/efeitos dos fármacos
5.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200964

RESUMO

For osteosarcoma (OS), the most common primary malignant bone tumor, overall survival has hardly improved over the last four decades. Especially for metastatic OS, novel therapeutic targets are urgently needed. A hallmark of cancer is aberrant metabolism, which justifies targeting metabolic pathways as a promising therapeutic strategy. One of these metabolic pathways, the NAD+ synthesis pathway, can be considered as a potential target for OS treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the classical salvage pathway for NAD+ synthesis, and NAMPT is overexpressed in OS. In this study, five OS cell lines were treated with the NAMPT inhibitor FK866, which was shown to decrease nuclei count in a 2D in vitro model without inducing caspase-driven apoptosis. The reduction in cell viability by FK866 was confirmed in a 3D model of OS cell lines (n = 3). Interestingly, only OS cells with low nicotinic acid phosphoribosyltransferase domain containing 1 (NAPRT1) RNA expression were sensitive to NAMPT inhibition. Using a publicly available (Therapeutically Applicable Research to Generate Effective Treatments (TARGET)) and a previously published dataset, it was shown that in OS cell lines and primary tumors, low NAPRT1 RNA expression correlated with NAPRT1 methylation around the transcription start site. These results suggest that targeting NAMPT in osteosarcoma could be considered as a novel therapeutic strategy, where low NAPRT expression can serve as a biomarker for the selection of eligible patients.


Assuntos
Acrilamidas/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , NAD/metabolismo , Osteossarcoma/tratamento farmacológico , Pentosiltransferases/antagonistas & inibidores , Piperidinas/farmacologia , Apoptose , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Proliferação de Células , Glioma/metabolismo , Glioma/patologia , Humanos , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Células Tumorais Cultivadas
6.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206141

RESUMO

The interaction of multi-LacNAc (Galß1-4GlcNAc)-containing N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers with human galectin-1 (Gal-1) and the carbohydrate recognition domain (CRD) of human galectin-3 (Gal-3) was analyzed using NMR methods in addition to cryo-electron-microscopy and dynamic light scattering (DLS) experiments. The interaction with individual LacNAc-containing components of the polymer was studied for comparison purposes. For Gal-3 CRD, the NMR data suggest a canonical interaction of the individual small-molecule bi- and trivalent ligands with the lectin binding site and better affinity for the trivalent arrangement due to statistical effects. For the glycopolymers, the interaction was stronger, although no evidence for forming a large supramolecule was obtained. In contrast, for Gal-1, the results indicate the formation of large cross-linked supramolecules in the presence of multivalent LacNAc entities for both the individual building blocks and the polymers. Interestingly, the bivalent and trivalent presentation of LacNAc in the polymer did not produce such an increase, indicating that the multivalency provided by the polymer is sufficient for triggering an efficient binding between the glycopolymer and Gal-1. This hypothesis was further demonstrated by electron microscopy and DLS methods.


Assuntos
Proteínas Sanguíneas/química , Galectina 1/química , Galectinas/química , Metacrilatos/química , Polímeros/química , Acrilamidas/química , Acrilamidas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Proteínas Sanguíneas/genética , Carboidratos/química , Microscopia Crioeletrônica , Galectina 1/genética , Galectinas/genética , Humanos , Ligantes , Metacrilatos/farmacologia , Polímeros/farmacologia , Ligação Proteica/efeitos dos fármacos
7.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070254

RESUMO

We evaluated the utility of optical redox imaging (ORI) to identify the therapeutic response of triple-negative breast cancers (TNBC) under various drug treatments. Cultured HCC1806 and MDA-MB-231 cells treated with FK866 (nicotinamide phosphoribosyltransferase (Nampt) inhibitor), FX11 (lactate dehydrogenase A inhibitor), paclitaxel, and their combinations were subjected to ORI, followed by imaging fluorescently labeled reactive oxygen species (ROS). Cell growth inhibition was measured by a cell viability assay. We found that both cell lines experienced significant NADH decrease and redox ratio (Fp/(NADH+Fp)) increase due to FK866 treatment; however, HCC1806 was much more responsive than MDA-MB-231. We further studied HCC1806 with the main findings: (i) nicotinamide riboside (NR) partially restored NADH in FK866-treated cells; (ii) FX11 induced an over 3-fold NADH increase in FK866 or FK866+NR pretreated cells; (iii) FK866 combined with paclitaxel caused synergistic increases in both Fp and the redox ratio; (iv) FK866 sensitized cells to paclitaxel treatments, which agrees with the redox changes detected by ORI; (v) Fp and the redox ratio positively correlated with cell growth inhibition; and (vi) Fp and NADH positively correlated with ROS level. Our study supports the utility of ORI for detecting the treatment responses of TNBC to Nampt inhibition and the sensitization effects on standard chemotherapeutics.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Citocinas , Nicotinamida Fosforribosiltransferase , Neoplasias de Mama Triplo Negativas , Acrilamidas/farmacologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Feminino , Humanos , Microscopia de Fluorescência , Naftalenos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/metabolismo , Oxirredução/efeitos dos fármacos , Piperidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/enzimologia , Neoplasias de Mama Triplo Negativas/patologia
8.
Cancer Sci ; 112(9): 3810-3821, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34145929

RESUMO

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, due to acquired resistance to EGFR-TKIs, even patients on third-generation osimertinib have a poor prognosis. Resistance mechanisms are still not fully understood. Here, we demonstrate that the increased expression of MUSASHI-2 (MSI2), an RNA-binding protein, is a novel mechanism for resistance to EGFR-TKIs. We found that after a long-term exposure to gefitinib, the first-generation EGFR-TKI lung cancer cells harboring the EGFR-TKI-sensitive mutations became resistant to both gefitinib and osimertinib. Although other mutations in EGFR were not found, expression levels of Nanog, a stemness core protein, and activities of aldehyde dehydrogenase (ALDH) were increased, suggesting that cancer stem-like properties were increased. Transcriptome analysis revealed that MSI2 was among the stemness-related genes highly upregulated in EGFR-TKI-resistant cells. Knockdown of MSI2 reduced cancer stem-like properties, including the expression levels of Nanog, a core stemness factor. We demonstrated that knockdown of MSI2 restored sensitivity to osimertinib or gefitinib in EGFR-TKI-resistant cells to levels similar to those of parental cells in vitro. An RNA immunoprecipitation (RIP) assay revealed that antibodies against MSI2 were bound to Nanog mRNA, suggesting that MSI2 increases Nanog expression by binding to Nanog mRNA. Moreover, overexpression of MSI2 or Nanog conferred resistance to osimertinib or gefitinib in parental cells. Finally, MSI2 knockdown greatly increased the sensitivity to osimertinib in vivo. Collectively, our findings provide proof of principle that targeting the MSI2-Nanog axis in combination with EGFR-TKIs would effectively prevent the emergence of acquired resistance.


Assuntos
Acrilamidas/farmacologia , Adenocarcinoma de Pulmão/metabolismo , Compostos de Anilina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe/farmacologia , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas de Ligação a RNA/metabolismo , Regulação para Cima , Células A549 , Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/patologia , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Gefitinibe/uso terapêutico , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/patologia , Mutação , Proteína Homeobox Nanog/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas de Ligação a RNA/genética , Transcriptoma , Transfecção
9.
Exp Cell Res ; 405(2): 112648, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34119493

RESUMO

The acute inflammatory stimulation occurring after a bone fracture regulates the repair and healing of local bone injury; however, under certain conditions, pyroptosis may occur in osteoblasts, which affects osteoblast proliferation and differentiation, thereby affecting the growth, development and morphological changes of bone tissue. The aim of the present study was to examine the effect of the pyroptosis inhibitor necrosulfonamide (NSA) on the proliferation and differentiation of osteoblasts and elucidate the underlying mechanism. The results revealed that NSA reversed the effects of ATP/lipopolysaccharide (LPS) on cell viability and pyroptosis, and on the mRNA and protein expression of pyroptosis-related genes. It also suppressed the secretion of IL-6, TNF-α and IL-1ß and reversed the effects of ATP/LPS on the activity of ALP and the mRNA expression of differentiation-related genes in osteoblasts. The fact that overexpression of caspase-1, gasdermin D (GSDMD) and NLRP3 abolished the effects of NSA on the viability and pyroptosis of osteoblasts, as well as the mRNA expression of differentiation-related genes and the activity of ALP in osteoblasts, indicated that NSA promoted the proliferation and differentiation of osteoblasts by inhibiting the NLRP3/caspase-1/GSDMD pyroptosis pathway. The present study provides proof supporting the potential application of NSA for improving the function of osteoblasts in fracture repair and indicates the value of the NLRP3/caspase-1/GSDMD pyroptosis pathway as a pharmaceutical target.


Assuntos
Acrilamidas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Sulfonamidas/farmacologia , Caspase 1/efeitos dos fármacos , Caspase 1/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia
10.
Nat Commun ; 12(1): 3697, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140482

RESUMO

Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.


Assuntos
Acrilamidas/administração & dosagem , Acrilamidas/farmacologia , Compostos de Anilina/administração & dosagem , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/dietoterapia , Quinazolinonas/administração & dosagem , Quinazolinonas/farmacologia , Acrilamidas/farmacocinética , Acrilamidas/toxicidade , Compostos de Anilina/farmacocinética , Compostos de Anilina/toxicidade , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Estudos de Coortes , Simulação por Computador , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Modelos Estatísticos , Modelos Teóricos , Mutação , Quinazolinonas/farmacocinética , Quinazolinonas/toxicidade
11.
J Photochem Photobiol B ; 221: 112238, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34130091

RESUMO

Nicotinamide adenine dinucleotide (NAD+) is a crucial coenzyme in energy production. The imbalance of NAD+ synthesis has been found to trigger age-related diseases, such as metabolic disorders, cancer, and neurodegenerative diseases. Also, UV irradiation induces NAD+ depletion in the skin. In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway and essential for NAD+ homeostasis. However, but few studies have focused on the role of NAMPT in response to UV irradiation. Here, we show that NAMPT prevents NAD+ depletion in epidermal keratinocytes to protect against the mild-dose UVA and UVB (UVA/B)-induced proliferation defects. We showed that poly(ADP-ribose) polymerase (PARP) inhibitor rescued the NAD+ depletion in UVA/B-irradiated human keratinocytes, confirming that PAPR transiently exhausts cellular NAD+ to repair DNA damage. Notably, the treatment with a NAMPT inhibitor exacerbated the UVA/B-induced loss of energy production and cell viability. Moreover, the NAMPT inhibitor abrogated the sirtuin-1 (SIRT1)-mediated deacetylation of p53 and significantly inhibited the proliferation of UVA/B-irradiated cells, suggesting that the NAMPT-NAD+-SIRT1 axis regulates p53 functions upon UVA/B stress. The supplementation with NAD+ intermediates, nicotinamide mononucleotide and nicotinamide riboside, rescued the UVA/B-induced phenotypes in the absence of NAMPT activity. Therefore, NAD+ homeostasis is likely essential for the protection of keratinocytes from UV stress in mild doses. Since the skin is continuously exposed to UVA/B irradiation, understanding the protective role of NAMPT in UV stress will help prevent and treat skin photoaging.


Assuntos
NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta , Acrilamidas/química , Acrilamidas/metabolismo , Acrilamidas/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA/efeitos da radiação , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacologia
12.
Toxicol Lett ; 348: 10-17, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34044055

RESUMO

Osimertinib is the only third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) approved by Food and Drug Administration (FDA). This study aimed to know the inhibitory effect of osimertinib on human UDP-glucosyltransferases (UGTs) and human liver microsomes (HLMs), as well as to identify its potential to cause drug-drug interaction (DDI) arising from the modulation of UGT activity. High inhibitory effect of osimertinib was shown towards UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A10, 2B7 and 2B15. Especially, osimertinib exhibited competitive inhibition against UGT1A1 with a Ki,u of 0.87 ± 0.12 µM. It also noncompetitively inhibited SN-38 glucuronidation in pooled HLMs with a Ki,u of 3.32 ± 0.25 µM. Results from quantitative prediction study indicated that osimertinib administered at 80 mg/day may result in a 4.83 % increase in the AUC of drugs mainly metabolized by UGT1A1, implying low risk of DDI via liver metabolism. However, the ratios of [I]gut/Ki,u are much higher than 11 in HLMs and recombinant UGT1A1, indicating a risk for interaction in intestine. The effects of osimertinib on intestinal UGT should be paid more attention on to avoid unnecessary clinical DDI risks.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Interações Medicamentosas , Glucuronosiltransferase/fisiologia , Humanos , Masculino , Microssomos Hepáticos/metabolismo
13.
Cancer Genet ; 256-257: 57-61, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33901930

RESUMO

The EGFR-A763_Y764insFQEA is a unique mutation among EGFR exon 20 insertion mutations in that it is associated with sensitivity to conventional EGFR-tyrosine kinase inhibitors. This mutation, which was not initially covered by conventional reverse transcription polymerase chain reaction (RT-PCR) genotyping method, has only been detected in clinical practice when a next-generation sequencing (NGS)-based cancer panel is implemented. We present the case of a female patient with recurrent lung adenocarcinoma from a lung tumor resected 10 years earlier. Sequential single-gene investigations and the OncomineTM Comprehensive Assay (ver.3) analysis of the recurrent tumor did not reveal any targetable driver mutations. However, the second NGS analysis with the OncoGuideTM NCC oncopanel found the EGFR-A763_Y764insFQEA mutation after tumor progression with carcinomatous lymphangiomatosis and multiple brain metastases. Osimertinib treatment improved her condition immediately. The identical EGFR-A763_Y764insFQEA mutation was detected in the tumor resected 10 years earlier. Based on this common mutation the patient was diagnosed with late recurrence of lung cancer harboring the EGFR-A763_Y764insFQEA mutation. The OncoGuideTM NCC oncopanel covered whole exons of the EGFR gene and was able to detect this mutation. In the present clinical practice, the EGFR-A763_Y764insFQEA mutation is the only treatable mutation among EGFR Ex.20 insertion mutations. We need to understand the gene mutation profile identified by each panel and consider reexamining them for this mutation.


Assuntos
Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Compostos de Anilina/uso terapêutico , Éxons/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutagênese Insercional/genética , Mutação/genética , Recidiva Local de Neoplasia/patologia , Acrilamidas/farmacologia , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/patologia , Idoso , Compostos de Anilina/farmacologia , Sequência de Bases , Encéfalo/diagnóstico por imagem , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/diagnóstico por imagem , Tórax/diagnóstico por imagem , Tomografia Computadorizada por Raios X
14.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924522

RESUMO

(1) Background: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable problem for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR-mutated lung cancer remains largely unknown. (2) Methods: Osimertinib- and afatinib-resistant EGFR-mutated lung cancer cells were established using a stepwise method. A microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells and evaluated by bioinformatics analysis through medical-industrial collaboration. (3) Results: Colorectal neoplasia differentially expressed (CRNDE) and DiGeorge syndrome critical region gene 5 (DGCR5) lncRNAs were highly expressed in EGFR-TKI-resistant cells by microarray analysis. RNA-protein binding analysis revealed eukaryotic translation initiation factor 4A3 (eIF4A3) bound in an overlapping manner to CRNDE and DGCR5. The CRNDE downregulates the expression of eIF4A3, mucin 1 (MUC1), and phospho-EGFR. Inhibition of CRNDE activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity, and restored sensitivity to EGFR-TKIs. (4) Conclusions: The results showed that CRNDE is associated with the development of resistance to EGFR-TKIs. CRNDE may be a novel therapeutic target to conquer EGFR-mutant NSCLC.


Assuntos
RNA Helicases DEAD-box/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Neoplasias Pulmonares/genética , Mucina-1/metabolismo , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , RNA Longo não Codificante/metabolismo , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Modelos Biológicos , Inibidores de Proteínas Quinases/uso terapêutico , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos
15.
Jpn J Clin Oncol ; 51(6): 956-965, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33829270

RESUMO

OBJECTIVE: A third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is the standard treatment for patients with non-small cell lung cancer harbouring mutant EGFR. Unfortunately, these patients inevitably acquire resistance to EGFR-TKI therapies, including osimertinib. However, the mechanism associated with this resistance remains unclear. METHODS: A 63-year-old Japanese female with lung adenocarcinoma underwent right upper lobectomy (pT1bN2M0 pStage IIIA, EGFR Ex21 L858R). She manifested post-operative tumour recurrence with multiple lung metastases 8 months later and began gefitinib treatment. The lung lesions re-grew 15 months later, and EGFR T790M mutation was detected in the lung metastasis re-biopsy. She was administered osimertinib; however, it relapsed with pleural effusion 16 months later. We isolated cells from the osimertinib-resistant pleural effusion to establish a novel cell line, ABC-31. RESULTS: Although the EGFR L858R mutation was detected in ABC-31 cells, the T790M mutation was lost. ABC-31 cells were resistant to EGFR-TKIs, including osimertinib. Phospho-receptor tyrosine kinase array revealed activation of the insulin-like growth factor 1 receptor (IGF1R), whereas overexpression of the IGF1R ligand, IGF2, induced IGF1R activation in ABC-31 cells. Combination therapy using EGFR-TKIs and IGF1R inhibitor acted synergistically in vitro. She was re-administered osimertinib since EGFR-TKIs and IGF1R inhibitor combination therapy was impossible in clinical practice. This had a slight and short-lived effect. CONCLUSIONS: Taken together, we have successfully established a new osimertinib-resistant lung adenocarcinoma cell line with activated IGF1R. These ABC-31 cells will help develop novel therapeutic strategies for patients with lung adenocarcinoma resistant to specific treatment via IGF1R activation.


Assuntos
Acrilamidas/farmacologia , Adenocarcinoma de Pulmão/genética , Compostos de Anilina/farmacologia , Neoplasias Pulmonares/genética , Receptor IGF Tipo 1/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia
16.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801927

RESUMO

BACKGROUND: Nuclear protein-1 (NUPR1, also known as p8/Com-1) is a transcription factor involved in the regulation of cellular stress responses, including serum starvation and drug stimulation. METHODS: We investigated the mechanism of NUPR1 nuclear translocation involving karyopherin ß1 (KPNB1), using a single-molecule binding assay and confocal microscopy. The cellular effects associated with NUPR1-KPNB1 inhibition were investigated by gene expression profiling and cell cycle analysis. RESULTS: The single-molecule binding assay revealed that KPNB1 bound to NUPR1 with a binding affinity of 0.75 nM and that this binding was blocked by the aminothiazole ATZ-502. Following doxorubicin-only treatment, NUPR1 was translocated to the nucleus in more than 90% and NUPR1 translocation was blocked by the ATZ-502 combination treatment in MDA-MB-231 with no change in NUPR1 expression, providing strong evidence that NUPR1 nuclear translocation was directly inhibited by the ATZ-502 treatment. Inhibition of KPNB1 and NUPR1 binding was associated with a synergistic anticancer effect (up to 19.6-fold) in various cancer cell lines. NUPR1-related genes were also downregulated following the doxorubicin-ATZ-502 combination treatment. CONCLUSION: Our current findings clearly demonstrate that NUPR1 translocation into the nucleus requires karyopherin ß1 binding. Inhibition of the KPNB1 and NUPR1 interaction may constitute a new cancer therapeutic approach that can increase the drug efficacy while reducing the side effects.


Assuntos
Acrilamidas/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzotiazóis/farmacologia , Doxorrubicina/farmacologia , Proteínas de Neoplasias/metabolismo , beta Carioferinas/metabolismo , Acrilamidas/química , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Benzotiazóis/química , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Sinergismo Farmacológico , Humanos , Células MCF-7 , Microscopia Confocal , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos
17.
Toxicol Appl Pharmacol ; 419: 115518, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33812963

RESUMO

Lung cancer is considered the main cause of cancer mortality worldwide. Osimertinib, a third-generation EGFR-TKI, has been approved and administrated for treating patients with either EGFR T790M mutation or EGFR sensitive mutation. However, resistance to osimertinib emerges and has been considered to be the main obstacle in lung cancer treatment. Polyphyllin I is isolated from the natural herb Paris polyphylla and exhibits anti-cancer activities. In the present study, we identify Polyphyllin I to reverse the resistance of osimertinib in vitro and in vivo. The results showed that Polyphyllin I reversed the resistance of osimertinib through promoting apoptosis, modulating the PI3K/Akt signaling, and regulating the expression of apoptosis-related proteins in osimertinib-resistant cell lines. In vivo study confirmed the results, showing that the tumor growth was significantly suppressed in the Polyphyllin I/osimertinib group compared to the osimertinib group. It has been clarified that Polyphyllin I could reverse the resistance of osimertinib in osimertinib-resistant non-small cell of lung cancer in vitro and in vivo. The underlying mechanism might be related to the downregulation of the PI3K/Akt signaling and increase of the expression of apoptosis-related proteins, suggesting that Polyphyllin I was a promising therapeutic agent for reversing the resistance of osimertinib.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Diosgenina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Diosgenina/farmacologia , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J BUON ; 26(1): 51-57, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33721431

RESUMO

PURPOSE: To explore the efficacy and safety of the third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) Osimertinib in the treatment of patients with first-generation EGFR-TKI-resistant advanced non-small cell lung cancer (NSCLC). METHODS: The clinical data of 84 patients with advanced NSCLC treated in our hospital from September 2016 to March 2018 were retrospectively analyzed. All patients had progressive disease (PD) after treatment with first-generation EGFR-TKI, and then they were treated with Osimertinib. The remission of disease was analyzed and evaluated after treatment, and the long-term survival and progression of disease were recorded via follow-up. The influencing factors for the patient's prognosis were explored using univariate and multivariate Cox regression analyses. RESULTS: The efficacy was evaluated in all patients at 4 weeks after treatment. There were 0 cases of complete response (CR), 34 cases (40.5%) of partial response (PR), 38 cases (45.2%) of stable disease (SD) and 12 cases (14.3%) of PD. The objective response rate (ORR) and the disease control rate (DCR) were 40.5% (34/84) and 85.7% (72/84), respectively. The main adverse reactions included diarrhea (34.5%), nausea and vomiting (14.3%), constipation (11.9%), rash (27.4%), skin itch (20.2%), loss of appetite (13.1%), oral ulcer (10.7%), hepatic dysfunction (2.4%) and bone marrow suppression, mostly of grade I-II, which could be significantly relieved after symptomatic treatment. The incidence rate of grade III and above adverse reactions was 9.5% (8/84). The dosage of Osimertinib was reduced in 2 cases due to adverse reactions, while other adverse reactions were improved after symptomatic treatment. The levels of vascular endothelial growth factor (VEGF) and carcinoembryonic antigen (CEA) obviously declined from 247.57±20.72 pg/mL and 11.20±1.38 µg/L before treatment to 134.84±14.37 pg/mL and 6.80±0.54 µg/L after treatment (p<0.05). The median overall survival (mOS) and median progression-free survival (mPFS) were 25.3 and 10.6 months, respectively. The 1-year OS rate was 79.8% (67/84), and the OS rate was 52.3% at the end of follow-up. Subgroup analysis showed found that heart disease and thrombosis complicated before treatment had significant impact on mOS (p=0.007, p=0.019). The results of multivariate Cox regression analysis revealed that heart disease and thrombosis complicated before treatment were independent risk factors affecting the patient's OS [HR=2.339 (95% CI: 1.448-5.674), p=0.031, HR=1.977 (95% CI: 1.152-2.365), p=0.020]. CONCLUSION: Osimertinib has definite efficacy in the treatment of patients with first-generation EGFR-TKI-resistant advanced NSCLC, with a low incidence rate of tolerable adverse reactions. The presence or absence of heart disease and thrombosis before treatment are independent influencing factors for the patient OS.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/farmacologia
19.
Biochem Pharmacol ; 188: 114516, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33713643

RESUMO

The overexpression of the human ATP-binding cassette (ABC) drug transporter ABCB1 (P-glycoprotein, P-gp) or ABCG2 (breast cancer resistance protein, BCRP) in cancer cells often contributes significantly to the development of multidrug resistance (MDR) in cancer patients. Previous reports have demonstrated that some epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could modulate the activity of ABCB1 and/or ABCG2 in human cancer cells, whereas some EGFR TKIs are transport substrates of these transporters. Almonertinib (HS-10296) is a promising, orally available third-generation EGFR TKI for the treatment of EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) in patients who have progressed on or after other EGFR TKI therapies. Additional clinical trials are currently in progress to study almonertinib as monotherapy and in combination with other agents in patients with NSCLC. In the present work, we found that neither ABCB1 nor ABCG2 confers significant resistance to almonertinib. More importantly, we discovered that almonertinib was able to reverse MDR mediated by ABCB1, but not ABCG2, in multidrug-resistant cancer cells at submicromolar concentrations by inhibiting the drug transport activity of ABCB1 without affecting its expression level. These findings are further supported by in silico docking of almonertinib in the drug-binding pocket of ABCB1. In summary, our study revealed an additional activity of almonertinib to re-sensitize ABCB1-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic drugs, which may be beneficial for cancer patients and warrant further investigation.


Assuntos
Acrilamidas/farmacologia , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Indóis/farmacologia , Pirimidinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/fisiologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/biossíntese , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Estrutura Secundária de Proteína
20.
Neurochem Res ; 46(5): 1291-1304, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33713324

RESUMO

Alleviating microglia-mediated neuroinflammation bears great promise to reduce neurodegeneration. Nicotinamide phosphoribosyltransferase (NAMPT) may exert cytokine-like effect in the brain. However, it remains unclear about role of NAMPT in microglial inflammation. Also, it remains unknown about effect of NAMPT inhibition on microglial inflammation. In the present study, we observed that FK866 (a specific noncompetitive NAMPT inhibitor) dose-dependently inhibited lipopolysaccharide (LPS)-induced proinflammatory mediator (interleukin (IL)-6, IL-1ß, inducible nitric oxide synthase, nitric oxide and reactive species) level increase in BV2 microglia cultures. FK866 also significantly inhibited LPS-induced polarization change in microglia. Furthermore, LPS significantly increased NAMPT expression and nuclear factor kappa B (NF-κB) phosphorylation in microglia. FK866 significantly decreased NAMPT expression and NF-κB phosphorylation in LPS-treated microglia. Finally, conditioned medium from microglia cultures co-treated with FK866 and LPS significantly increased SH-SY5Y and PC12 cell viability compared with conditioned medium from microglia cultures treated with LPS alone. Our study strongly indicates that NAMPT may be a promising target for microglia modulation and NAMPT inhibition may attenuate microglial inflammation.


Assuntos
Acrilamidas/farmacologia , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Microglia/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Ratos
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