RESUMO
Purpose: Sinomenine (SIN) is commonly used in Traditional Chinese Medicine (TCM) as a respected remedy for rheumatoid arthritis (RA). Nevertheless, the therapeutic mechanism of SIN in RA remains incompletely understood. This study aimed to delve into the molecular mechanism of SIN in the treatment of RA. Methods: The potential targets of SIN were predicted using the TCMSP server, STITCH database, and SwissTarget Prediction. Differentially expressed genes (DEGs) in RA were obtained from the GEO database. Enrichment analyses and molecular docking were conducted to explore the potential mechanism of SIN in the treatment of RA. In vitro and in vivo studies were conducted to validate the intervention effects of SIN on rheumatoid arthritis, as determined through network pharmacology analyses. Results: A total of 39 potential targets associated with the therapeutic effects of SIN in RA were identified. Enrichment analysis revealed that these potential targets are primarily enriched in PI3K-Akt signaling pathway, and the molecular docking suggests that SIN may act on specific proteins in the pathway. Experimental results have shown that exposure to SIN inhibits cytokine secretion, promotes apoptosis, reduces metastasis and invasion, and blocks the activation of the PI3K-Akt signaling pathway in RA fibroblast-like synoviocytes (RA-FLS). Moreover, SIN treatment alleviated arthritis-related symptoms and regulated the differentiation of CD4+ T cells in the spleen of collagen-induced arthritis (CIA) mice. Conclusion: By utilizing network pharmacology, molecular modeling, and in vitro/in vivo validation, this study demonstrates that SIN can alleviate RA by inhibiting the PI3K-Akt signaling pathway. These findings enhance the understanding of the therapeutic mechanisms of SIN in RA, offering a stronger theoretical foundation for its future clinical application.
Assuntos
Artrite Reumatoide , Simulação de Acoplamento Molecular , Morfinanos , Farmacologia em Rede , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Morfinanos/farmacologia , Morfinanos/química , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Camundongos , Animais , Transdução de Sinais/efeitos dos fármacos , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Masculino , Antirreumáticos/farmacologia , Antirreumáticos/química , Células Cultivadas , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Experimental/metabolismo , Camundongos Endogâmicos DBARESUMO
Novel thieno[2,3-d]pyrimidine analogues were designed, synthesized and evaluated for anti-proliferative activity against HepG-2, PC-3 and MCF-7 cancer cell lines. In addition, WI-38 normal cell line was used to explore the safety of all the tested compounds. Compounds 2 (IC50 = 4.29 µM HePG-2, 10.84 µM MCF-7), 6 (IC50 = 14.86 µM HePG-2, 8.04 µM PC-3 and 12.90 µM MCF-7) and 17 (IC50 = 9.98 µM HePG-2, 33.66 µM PC-3 and 14.62 µM MCF-7) were the most promising candidates on the tested cancer cells with high selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where compound 2 inhibited VEGFR-2 and AKT at IC50 = 0.161 and 1.06 µM, respectively, Furthermore, derivative 6 inhibited VEGFR-2 and AKT at IC50 = 0.487 and 0.364 µM, respectively, while compound 17 showed IC50 = 0.164 and 0.452 µM, respectively. Moreover, compounds 2, 6 resulted in G1 phase cell cycle arrest while candidate 17 arrest cell cycle at G2/M phase. Similar to the apoptosis results, compound 17 showed the highest autophagic induction among the evaluated derivatives. Finally, docking studies were conducted to assess the binding patterns of these active derivatives. The results showed that the binding patterns inside the active sites of both the VEGFR-2 and AKT-1 (allosteric pocket) crystal structures were identical to the reference ligands.
Assuntos
Antineoplásicos , Apoptose , Autofagia , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt , Pirimidinas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Pirimidinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Apoptose/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Autofagia/efeitos dos fármacos , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estrutura Molecular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Simulação de Acoplamento Molecular , Linhagem Celular TumoralRESUMO
Increases in de novo lipogenesis that disturbed lipid homeostasis and caused lipid accumulation are a major cause of NAFLD and obesity. SREBP1 is a crucial regulatory factor controlling the expression of rate-limiting enzymes of lipid synthesis. A reduction in SREBP1expression can reduce lipid accumulation. Thus, we utilized an SREBP1-luciferase-KI HEK293 cell line constructed by our lab to screen 200 kinds of epigenetic drugs for their ability to downregulate SREBP1expression. BI-7273, an inhibitor of bromodomain-containing protein 9 (BRD9), was screened and found to decrease SREBP1 expression. What is more, BI-7273 has been confirmed that it could reduce lipid accumulation in HepG2 cells by BODIPY staining, and significantly decrease the protein expression of SREBP1 and FASN. To explore the potential mechanism BI-7273 reducing lipid accumulation, RNA sequencing (RNA-seq) was performed and demonstrated that BI-7273 reduced lipid accumulation by downregulating the AKT/mTOR/SREBP1 pathway in vitro. Finally, these results were verified in NAFLD and obesity mouse model induced by high fat diet (HFD). The results indicated that BI-7273 could decrease mouse body weight and improve insulin sensitivity, but also exhibited a strong negative correlation with serum lipid levels, and also demonstrated that BI-7273 reduced lipid accumulation via AKT/mTOR/SREBP1 pathway in vivo. In conclusion, our results revealed that BI-7273 decreases lipid accumulation by downregulating the AKT/mTOR/SREBP1 pathway in vivo and in vitro. This is the first report demonstrating the protective effect of this BRD9 inhibitor against NAFLD and obesity. BRD9 may be a novel target for the discovery of effective drugs to treat lipid metabolism disorders.
Assuntos
Metabolismo dos Lipídeos , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1 , Serina-Treonina Quinases TOR , Fatores de Transcrição , Animais , Humanos , Masculino , Camundongos , Proteínas que Contêm Bromodomínio , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Células HEK293 , Células Hep G2 , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Fatores de Transcrição/antagonistas & inibidoresRESUMO
An open-label, single-center, phase I study was conducted to determine the absolute bioavailability and absorption, distribution, metabolism, and excretion of capivasertib-a potent, selective AKT serine/threonine kinase inhibitor-in healthy males. In part 1, six participants received a single oral dose of capivasertib (400 mg; tablets) followed by a [14C]-radiolabeled intravenous microdose of capivasertib (100 µg). After a 14-day washout, five of the participants proceeded to part 2 and received a single oral dose of [14C]capivasertib (400 mg; solution). In part 1, median time of maximum observed concentration for capivasertib was 1.7 hours, geometric mean terminal elimination half-life was 12.9 hours, and absolute bioavailability was estimated at 28.6% (90% confidence interval, 23.9 to 34.2). In part 2, a high proportion of the administered radioactivity was recovered over the 168-hour sampling period [mean recovery: 95.1% (feces, 50.4%; urine, 44.7%)]. Unchanged capivasertib in urine accounted for 7.4% of the total dose and 21.1% of the systemically available drug. Geometric mean renal clearance was 8.3 L/h, suggesting active tubular secretion. Twelve metabolites were identified in plasma. M11 (AZ14102143)-the glucuronide conjugate of capivasertib, inactive as an AKT serine/threonine kinase inhibitor-was the most abundant, accounting for a mean 78.4% of the plasma drug-related area under the curve. Of 22 metabolites identified in excreta, M11 was the most abundant (mean 28.2% of administered dose), indicating direct glucuronidation as one of the major routes of metabolism. No new safety concerns were identified. SIGNIFICANCE STATEMENT: This study provides characterization of the pharmacokinetics of capivasertib-a potent, selective AKT serine/threonine kinase (AKT) inhibitor-including absolute bioavailability, mass balance, and metabolic fate in humans; the findings are being used to inform further clinical development. Absolute bioavailability was estimated at 28.6%, and mean recovery of the administered dose in excreta over 168 hours was 95.1%. M11 (AZ14102143)-the glucuronide conjugate, inactive as an AKT inhibitor-was the most abundant identified metabolite in plasma and excreta.
Assuntos
Disponibilidade Biológica , Voluntários Saudáveis , Humanos , Masculino , Adulto , Adulto Jovem , Administração Oral , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Distribuição Tecidual , Pirróis/farmacocinética , Pirróis/administração & dosagem , Pirróis/metabolismo , Pirróis/urina , Pirróis/sangue , Pessoa de Meia-Idade , Meia-Vida , Fezes/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/farmacocinética , Pirimidinas/sangue , Pirimidinas/administração & dosagemRESUMO
In search of small molecules for targeted therapy of non-small cell lung carcinoma (NSCLC), an efficient four-step synthetic route was followed for the synthesis of new imidazothiazole-hydrazone hybrids, which were assessed for their cytotoxic effects on human lung adenocarcinoma (A549) and human lung fibroblast (CCD-19Lu) cells. Among them, compounds 4, 6, 13, 16, 17 and 21 exhibited selective cytotoxic activity against A549 cell line. In vitro mechanistic studies were performed to assess their effects on apoptosis, caspase-3, cell cycle, EGFR and Akt in A549 cells. Compounds 6, 16, 17 and 21 promoted apoptotic cell death more than erlotinib. According to the in vitro data, it is quite clear that compound 6 promotes apoptosis through caspase-3 activation and arrests the cell cycle at the G0/G1 phase in A549 cells. Compounds 16 and 17 arrested the cell cycle at the S phase, whereas compounds 4, 13 and 21 caused the cell cycle arrest at the G2/M phase. The most effective EGFR inhibitor in this series was found as compound 13, followed by compounds 17 and 16. Furthermore, Akt inhibitory effects of compounds 16 and 17 in A549 cells were close to that of GSK690693. In particular, it can be concluded that the cytotoxic and apoptotic effects of compounds 16 and 17 are associated with their inhibitory effects on both EGFR and Akt. Molecular docking studies suggest that compounds 16 and 17 interact with crucial amino acid residues in the binding sites of human EGFR (PDB ID: 1M17) and Akt2 (PDB ID: 3D0E). Based on the in silico data, both compounds are predicted to possess favorable oral bioavailability and drug-likeness. Further studies are required to benefit from these compounds as anticancer agents for targeted therapy of NSCLC.
Assuntos
Antineoplásicos , Apoptose , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Hidrazonas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt , Humanos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Hidrazonas/farmacologia , Hidrazonas/química , Hidrazonas/síntese química , Relação Estrutura-Atividade , Apoptose/efeitos dos fármacos , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/síntese química , Imidazóis/farmacologia , Imidazóis/química , Imidazóis/síntese química , Simulação de Acoplamento Molecular , Relação Dose-Resposta a Droga , Ciclo Celular/efeitos dos fármacosRESUMO
In this study, seven isoniazid-hydrazone derivatives (3a-g) were synthesized and their structures elucidated by chromatographic techniques, and then the antiproliferative effects of these compounds on various cancer cells were tested. The advanced anticancer mechanism of the most potent compound was then investigated. Antiproliferative activities of the synthesized compounds were evaluated on human breast cancer MCF-7, lung cancer A-549, colon cancer HT-29, and non-cancerous mouse fibroblast 3T3-L1 cell lines by XTT assay. Flow cytometry analysis were carried out to determine cell cycle distribution, apoptosis, mitochondrial membrane potential, multi-caspase activity, and expression of PI3K/AKT signaling pathway. The XTT results showed that all the title molecules displayed cytotoxic activity at varying strengths in different dose ranges, and among them, the strongest cytotoxic effect and high selectivity were exerted by 3d against MCF-7 cells with the IC50 value of 11.35 µM and selectivity index of 8.65. Flow cytometry results revealed that compound 3d induced apoptosis through mitochondrial membrane disruption and multi-caspase activation in MCF-7 cells. It also inhibited the cell proliferation via inhibition of expression of PI3K/AKT and arrested the cell cycle at G0/G1 phase. In conclusion, all these data disclosed that among the synthesized compounds, 3d is notable for in vivo anticancer studies.
Assuntos
Antineoplásicos , Apoptose , Caspases , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Hidrazonas , Isoniazida , Mitocôndrias , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proliferação de Células/efeitos dos fármacos , Hidrazonas/farmacologia , Hidrazonas/química , Hidrazonas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Caspases/metabolismo , Isoniazida/farmacologia , Isoniazida/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Camundongos , AnimaisRESUMO
INTRODUCTION: Incorporation of AKT inhibitors into adjuvant therapy for advanced or metastatic breast cancer has improved clinical outcomes. However, the safety of AKT inhibitors should be better evaluated, given the possibility of prolonging survival and impacting patient quality of life. Our aim was to assess how the addition of AKT inhibitors to adjuvant therapy affects treatment-related adverse events. METHODS: We evaluated binary outcomes with risk ratios (RRs), with 95% confidence intervals (CIs). We used DerSimonian and Laird random-effect models for all endpoints. Heterogeneity was assessed using I2 statistics. R, version 4.2.3, was used for statistical analyses. RESULTS: A total of seven RCTs comprising 1619 patients with BC. The adverse effects that show significance statistical favoring the occurrence of adverse effects in AKT inhibitor were diarrhea (RR 3.05; 95% CI 2.48-3.75; p < 0.00001; I2 = 49%), hyperglycemia (RR 3.4; 95% CI 1.69-6.83; p = 0.00058; I2 = 75%), nausea (RR 1.69; 95% CI 1.34-2.13; p = 0.000008; I2 = 42%), rash (RR 2.79; 95% CI 1.49-5.23; p = 0.0013; I2 = 82%), stomatitis (RR 2.24; 95% CI 1.69-2.97; p < 0.00001; I2 = 16%) and vomiting (RR 2.99; 95% CI 1.85-4.86; p = 0.00009; I2 = 42%). There was no significant difference between the groups for alopecia (p = 0.80), fatigue (p = 0.087), and neuropathy (p = 0.363380). CONCLUSION: The addition of AKT inhibitors to adjuvant therapy was associated with an increase in treatment-related adverse events. These results provide safety information for further clinical trials evaluating AKT inhibitor therapy for patients with metastatic BC. Clinicians should closely monitor patients for treatment-related adverse events to avoid discontinuation of therapy and morbidity caused by these early-stage therapies.
Assuntos
Neoplasias da Mama , Proteínas Proto-Oncogênicas c-akt , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Neoplasias da Mama/tratamento farmacológico , Feminino , Quimioterapia Adjuvante , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêuticoRESUMO
PURPOSE: The aim of this study was to quantitatively compare the efficacy and safety of CDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors for ER+/HER2- metastatic breast cancer. METHODS: A parametric survival function was used to analyze the time course of overall survival (OS) and progression-free survival (PFS). The objective response rate (ORR) and the incidence of any grade and grade 3-4 adverse events were summarized using the random-effects model of a single-arm meta-analysis. RESULTS: This study included 44 arms from 48 publications, with a total sample size of 7881 patients. Our study revealed that CDK4/6 inhibitors had a median OS of 40.7 months, a median PFS of 14.8 months, and an ORR of 40%, whereas PI3K/AKT/mTOR inhibitors had a median OS of 29.8 months, a median PFS of 8.3 months, and an ORR of 20%. Additionally, this study also found that the proportion of patients with visceral metastases and specific endocrine therapy used in combination significantly impact OS and PFS. In terms of adverse events, CDK4/6 inhibitors exhibited a relatively high incidence of hematological adverse events. CONCLUSION: Our study provides solid quantitative evidence for the first-line recommendation of CDK4/6 inhibitors combined with endocrine therapy for ER+/HER2- metastatic breast cancer in clinical guidelines.
Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Receptor ErbB-2 , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Intervalo Livre de Progressão , Metástase NeoplásicaRESUMO
Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (â¼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.
Assuntos
Glicogênio Sintase Quinase 3 beta , Neoplasias , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Humanos , Criança , Adolescente , Neoplasias/tratamento farmacológico , Neoplasias/genética , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de MTOR/uso terapêutico , Inibidores de MTOR/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
The mitogen-activated protein kinase (MAPK/ERK) pathway is pivotal in controlling the proliferation and survival of melanoma cells. Several mutations, including those in BRAF, exhibit an oncogenic effect leading to increased cellular proliferation. As a result, the combination therapy of a MEK inhibitor with a BRAF inhibitor demonstrated higher efficacy and lower toxicity than BRAF inhibitor alone. This combination has become the preferred standard of care for tumors driven by BRAF mutations. Aldehyde dehydrogenase 1A1 (ALDH1A1) is a known marker of stemness involved in drug resistance in several type of tumors, including melanoma. This study demonstrates that melanoma cells overexpressing ALDH1A1 displayed resistance to vemurafenib and trametinib through the activation of PI3K/AKT signaling instead of MAPK axis. Inhibition of PI3K/AKT signaling partially rescued sensitivity to the drugs. Consistently, pharmacological inhibition of ALDH1A1 activity downregulated the activation of AKT and partially recovered responsiveness to vemurafenib and trametinib. We propose ALDH1A1 as a new potential target for treating melanoma resistant to MAPK/ERK inhibitors.
Assuntos
Família Aldeído Desidrogenase 1 , Resistencia a Medicamentos Antineoplásicos , Melanoma , Células-Tronco Neoplásicas , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt , Retinal Desidrogenase , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Linhagem Celular Tumoral , Família Aldeído Desidrogenase 1/metabolismo , Família Aldeído Desidrogenase 1/genética , Retinal Desidrogenase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Pirimidinonas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Piridonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Vemurafenib/farmacologia , Aldeído Desidrogenase/metabolismo , Aldeído Desidrogenase/antagonistas & inibidores , Aldeído Desidrogenase/genética , Antineoplásicos/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , FenótipoRESUMO
BACKGROUND: Camptothecin (CPT), a pentacyclic alkaloid with antitumor properties, is derived from the Camptotheca acuminata. Topotecan and irinotecan (CPT derivatives) were first approved by the Food and Drug Administration for cancer treatment over 25 years ago and remain key anticancer drugs today. However, their use is often limited by clinical toxicity. Despite extensive development efforts, many of these derivatives have not succeeded clinically, particularly in their effectiveness against pancreatic cancer which remains modest. AIM OF THE STUDY: This study aimed to evaluate the therapeutic activity of FLQY2, a CPT derivative synthesized in our laboratory, against pancreatic cancer, comparing its efficacy and mechanism of action with those of established clinical drugs. METHODS: The cytotoxic effects of FLQY2 on cancer cells were assessed using an MTT assay. Patient-derived organoid (PDO) models were employed to compare the sensitivity of FLQY2 to existing clinical drugs across various cancers. The impact of FLQY2 on apoptosis and cell cycle arrest in Mia Paca-2 pancreatic cancer cells was examined through flow cytometry. Transcriptomic and proteomic analyses were conducted to explore the underlying mechanisms of FLQY2's antitumor activity. Western blotting was used to determine the levels of proteins regulated by FLQY2. Additionally, the antitumor efficacy of FLQY2 in vivo was evaluated in a pancreatic cancer xenograft model. RESULTS: FLQY2 demonstrated (1) potent cytotoxicity; (2) superior tumor-suppressive activity in PDO models compared to current clinical drugs such as gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infinitinib, and lenvatinib; (3) significantly greater tumor inhibition than paclitaxel liposomes in a pancreatic cancer xenograft model; (4) robust antitumor effects, closely associated with the inhibition of the TOP I and PDK1/AKT/mTOR signaling pathways. In vitro studies revealed that FLQY2 inhibited cell proliferation, colony formation, induced apoptosis, and caused cell cycle arrest at nanomolar concentrations. Furthermore, the combination of FLQY2 and gemcitabine exhibited significant inhibitory and synergistic effects. CONCLUSION: The study confirmed the involvement of topoisomerase I and the PDK1/AKT/mTOR pathways in mediating the antitumor activity of FLQY2 in treating Mia Paca-2 pancreatic cancer. Therefore, FLQY2 has potential as a novel therapeutic option for patients with pancreatic cancer.
Assuntos
Antineoplásicos , Apoptose , Camptotecina , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Camptotecina/farmacologia , Camptotecina/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Animais , Camundongos , Apoptose/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Piruvato Desidrogenase Quinase de Transferência de Acetil/antagonistas & inibidores , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Camundongos Nus , Células Tumorais Cultivadas , Linhagem Celular TumoralRESUMO
Azaphilones represent a particular group of fascinating pigments from fungal source, with easier industrialization and lower cost than the traditional plant-derived pigments, and they also display a wide range of pharmacological activities. Herein, 28 azaphilone analogs, including 12 new ones, were obtained from the fermentation culture of a marine fungus Penicillium sclerotium UJNMF 0503. Their structures were elucidated by MS, NMR and ECD analyses, together with NMR and ECD calculations and biogenetic considerations. Among them, compounds 1 and 2 feature an unusual natural benzo[d][1,3]dioxepine ring embedded with an orthoformate unit, while 3 and 4 represent the first azaphilone examples incorporating a novel rearranged 5/6 bicyclic core and a tetrahydropyran ring on the side chain, respectively. Our bioassays revealed that half of the isolates exhibited neuroprotective potential against H2O2-induced injury on RSC96 cells, while compound 13 displayed the best rescuing capacity toward the cell viability by blocking cellular apoptosis, which was likely achieved by upregulating the PI3K/Akt signaling pathway.
Assuntos
Apoptose , Benzopiranos , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio , Fármacos Neuroprotetores , Penicillium , Fosfatidilinositol 3-Quinases , Pigmentos Biológicos , Proteínas Proto-Oncogênicas c-akt , Apoptose/efeitos dos fármacos , Penicillium/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Pigmentos Biológicos/farmacologia , Pigmentos Biológicos/química , Pigmentos Biológicos/isolamento & purificação , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/antagonistas & inibidores , Estrutura Molecular , Benzopiranos/farmacologia , Benzopiranos/química , Benzopiranos/isolamento & purificação , Relação Estrutura-Atividade , Animais , Sobrevivência Celular/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND AND OBJECTIVES: Despite significant progress in biomedical research, the rate of success in oncology drug development remains inferior to that of other therapeutic fields. Mechanistic models provide comprehensive understanding of the therapeutic effects of drugs, which is crucial for designing effective clinical trials. This study was performed to acquire a better understanding of PI3K-AKT-TOR pathway modulation and preclinical to clinical translational bridging for a specific compound, apitolisib (PI3K/mTOR inhibitor), by developing integrated mechanistic models. METHODS: Integrated pharmacokinetic (PK)-pharmacodynamic (PD)-efficacy models were developed for xenografts bearing human renal cell adenocarcinoma and for patients with solid tumors (phase 1 studies) to characterize relationships between exposure of apitolisib, modulation of the phosphorylated Akt (pAkt) biomarker triggered by inhibition of the PI3K-AKT-mTOR pathway, and tumor response. RESULTS: Both clinical and preclinical integrated models show a steep sigmoid curve linking pAkt inhibition to tumor growth inhibition and quantified that a minimum of 35-45% pAkt modulation is required for tumor shrinkage in patients, based on platelet-rich plasma surrogate matrix and in xenografts based on tumor tissue matrix. Based on this relationship between targeted pAkt modulation and tumor shrinkage rate, it appeared that a constant pAkt inhibition of 61% and 65%, respectively, would be necessary to achieve tumor stasis in xenografts and patients. CONCLUSIONS: These results help when it comes to evaluating the translatability of the preclinical analysis to the clinical target, and provide information that will enhance the value of future preclinical translational dose-finding and dose-optimization studies to accelerate clinical drug development. TRIAL REGISTRY: ClinicalTrials.gov NCT00854152 and NCT00854126.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Inibidores de MTOR , Inibidores de Fosfoinositídeo-3 Quinase , Animais , Feminino , Humanos , Camundongos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias Renais/tratamento farmacológico , Inibidores de MTOR/uso terapêutico , Inibidores de MTOR/farmacologia , Inibidores de MTOR/farmacocinética , Neoplasias/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Estudos Retrospectivos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Diabetic mellitus (DM) is a chronic disorder, and type 2 DM (T2DM) is the most prevalent among all categories (nearly 90%) across the globe every year. With the availability of potential drugs, the prevalence rate has remained uncontrollable, while natural resources showed a promising potency, and exploring such potential candidates at the preclinical stage is essential. An extensive literature search selected 89 marine and plant-derived indole derivatives with anti-inflammatory, antioxidant, lipid-lowering, etc., activities. However, as we know, drugs have not been able to convert from 'lead' to 'mainstream' due to inadequate drug-ability profiles, as our systematic investigation proved and selected herdmanine_A (HERD_A) and penerpene_D (PENE_D) as the most potential antidiabetic candidates from the library of indole derivatives. Based on our previous network pharmacology study, we selected three new target enzymes: Acetyl-CoA carboxylase 2 (ACACB; PDB ID: 3JRX), cyclin-dependent kinase 4 (CDK4; PDB ID: 3G33), and alpha serine/threonine-protein kinase 1 (AKT1; PDB ID: 3O96) to assess the antidiabetic potency of selected indole derivatives through binding energy or docking score. To conduct molecular docking studies with these enzymes, we used the PyRx-AutoDock platform. Furthermore, molecular dynamic simulation at 100â¯ns, physicochemical analysis, pharmacokinetics, toxicity assessment, and drug-likeness evaluation suggested that HERD_A and penerpene PENE_D were the most potent inhibitors against AKT1 compared to koenimbine (most potential based on the recorded IC50 value) and murrayakonine_A (most potential based on the docking score). In summary, HERD_A and/or PENE_D have the potential to be used as alternative therapeutic agent for the treatment of diabetes after some pharmacological investigation.
Assuntos
Produtos Biológicos , Biologia Computacional , Hipoglicemiantes , Indóis , Proteínas Proto-Oncogênicas c-akt , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Indóis/química , Indóis/farmacologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismoRESUMO
Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context of cancer, overactive Akt promotes cell survival and proliferation. This has spurred extensive research into developing Akt inhibitors as potential therapeutic agents to disrupt aberrant Akt signaling. Akt inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric inhibitors (CAAIs). ATP-competitive inhibitors compete with ATP for binding to Akt, allosteric inhibitors interact with the Pleckstrin homology (PH) domain, and covalent-allosteric inhibitors form covalent bonds, making them more potent and selective. Notably, capivasertib (AZD5363), a potent ATP-competitive Akt inhibitor, received FDA approval in November 2023 for use in combination with the estrogen receptor degrader fulvestrant to treat breast cancer. Challenges remain, including improving selectivity, identifying biomarkers to tailor treatments, and enhancing therapeutic efficacy while minimizing adverse effects. Particularly covalent-allosteric inhibitors hold promise for future more effective and personalized treatments.
Assuntos
Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt , Pirimidinas , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Regulação Alostérica/efeitos dos fármacos , Aprovação de Drogas , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Pirróis/química , Pirróis/farmacologia , Pirróis/síntese química , AnimaisRESUMO
Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cervical cancer treatment. In this study, we designed and synthesized a series of benzimidazole derivatives and evaluated their anti-cervical cancer activity. Compound 4r exhibited strong antiproliferative activity in different cervical cancer cell lines HeLa, SiHa and Ca Ski, and relative lower cytotoxicity to normal hepatic and renal cell lines LO2 and HEK-293t (IC50 values were at 21.08 µM and 23.96 µM respectively). Its IC50 value was at 3.38 µM to the SiHa cells. Further mechanistic studies revealed that 4r induced apoptosis, arrested cell cycle in G2/M phase, suppressed PI3K/Akt/mTOR pathway and inhibit the polymerization of tubulin. Molecular docking study suggested that 4r formed key H-bonds action with PI3Kα (PDB ID:8EXU) and tubulin (PDB ID:1SA0). Zebrafish acute toxicity experiments showed that high concentrations of 4r did not cause death or malformation of zebrafish embryos. All these results demonstrated that 4r would be a promising lead candidate for further development of novel PI3K and tubulin dual inhibitors in cervical cancer treatment.
Assuntos
Antineoplásicos , Benzimidazóis , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Moduladores de Tubulina , Tubulina (Proteína) , Neoplasias do Colo do Útero , Peixe-Zebra , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Benzimidazóis/farmacologia , Benzimidazóis/química , Benzimidazóis/síntese química , Tubulina (Proteína)/metabolismo , Proliferação de Células/efeitos dos fármacos , Animais , Relação Estrutura-Atividade , Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Estrutura Molecular , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacosRESUMO
INTRODUCTION: Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein-protein interaction networks for PI3K and AKT show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of PI3K/AKT in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of 35 inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions for developing combinational therapy and PROTACs of PI3K and AKT inhibitors are also discussed. AREA COVERED: This review covers clinical trial reports and patent literature on inhibitors of PI3K and AKT published between 2020 and 2023. EXPERT OPINION: To address drug resistance and drug toxicity of inhibitors of PI3K and AKT, it is highly desirable to design and develop subtype-selective PI3K inhibitors or subtype-selective AKT1 inhibitors to minimize toxicity or to develop allosteric drugs that can form covalent bonds. The development of PROTACs of PI3Kα or AKT helps to reduce off-target toxicities.
Assuntos
Antineoplásicos , Desenho de Fármacos , Desenvolvimento de Medicamentos , Neoplasias , Patentes como Assunto , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Humanos , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Animais , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Resistencia a Medicamentos Antineoplásicos , Fosfatidilinositol 3-Quinases/metabolismo , Proliferação de Células/efeitos dos fármacos , Terapia de Alvo MolecularRESUMO
Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It has higher aggressiveness and metastasis than other subtypes, with limited effective therapeutic strategies, leading to a poor prognosis. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway is prevalently over-activated in human cancers and contributes to breast cancer (BC) growth, survival, proliferation, and angiogenesis, which could be an interesting therapeutic target. This review summarizes the PI3K/AKT/mTOR signaling pathway activation mechanism in TNBC and discusses the relationship between its activation and various TNBC subtypes. We also report the latest clinical studies on kinase inhibitors related to this pathway for treating TNBC. Our review discusses the issues that need to be addressed in the clinical application of these inhibitors.
Assuntos
Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Feminino , Fosfatidilinositol 3-Quinases/metabolismo , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de MTOR/uso terapêutico , Inibidores de MTOR/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
BACKGROUND: Colorectal cancer (CRC) remains a significant contributor to mortality, often exacerbated by metastasis and chemoresistance. Novel therapeutic strategies are imperative to enhance current treatments. The dysregulation of the PI3K/Akt signaling pathway is implicated in CRC progression. This study investigates the therapeutic potential of Wortmannin, combined with 5-fluorouracil (5-FU), to target the PI3K/Akt pathway in CRC. METHODS: Anti-migratory and antiproliferative effects were assessed through wound healing and MTT assays. Apoptosis and cell cycle alterations were evaluated using Annexin V/Propidium Iodide Apoptosis Assay. Wortmannin's impact on the oxidant/antioxidant equilibrium was examined via ROS, SOD, CAT, MDA, and T-SH levels. Downstream target genes of the PI3K/AKT pathway were analyzed at mRNA and protein levels using RTPCR and western blot, respectively. RESULTS: Wortmannin demonstrated a significant inhibitory effect on cell proliferation, modulating survivin, cyclinD1, PI3K, and p-Akt. The PI3K inhibitor attenuated migratory activity, inducing E-cadherin expression. Combined Wortmannin with 5-FU induced apoptosis, increasing cells in sub-G1 via elevated ROS levels. CONCLUSION: This study underscores Wortmannin's potential in inhibiting CRC cell growth and migration through PI3K/Akt pathway modulation. It also highlights its candidacy for further investigation as a promising therapeutic option in colorectal cancer treatment.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Neoplasias Colorretais , Ensaios de Seleção de Medicamentos Antitumorais , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Wortmanina , Humanos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Wortmanina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Relação Dose-Resposta a Droga , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Relação Estrutura-Atividade , Estrutura Molecular , Fluoruracila/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Movimento Celular/efeitos dos fármacosRESUMO
Citronella and Nutmeg are two common spices used for seasoning and medicinal purposes, both of which have significant economic value. This study aimed to investigate whether Citronella essential oil and Nutmeg essential oil (NEO) can ameliorate monosodium urate (MSU)-induced gouty arthritis in rats and the potential mechanisms. The results showed that CEO and NEO reduced swelling and redness at joint sites, inhibited neutrophil infiltration, and limited proinflammatory mediator secretion in mice with MSU-induced gouty arthritis. Based on the results of network pharmacology, molecular docking, and western blotting, CEO and NEO may exert anti-gouty arthritis effects by reducing the expression of reactive oxygen species and oxidative stress and downregulating the phosphorylation of the PI3K/AKT/mTOR signaling pathway, thereby inhibiting the production of the NLRP3 inflammasome and inhibiting the production of inflammatory cytokines. Therefore, these two essential oils show potential for use as adjuvant treatments for gouty arthritis in specific aromatherapy products or food seasonings.