ABSTRACT
The extracellular signal-regulated kinases-1 and 2 (ERK1/2) are ubiquitous regulators of many cellular functions, including proliferation, differentiation, migration, and cell death. ERK1/2 regulate cell functions by phosphorylating a diverse collection of protein substrates consisting of other kinases, transcription factors, structural proteins, and other regulatory proteins. ERK1/2 regulation of cell functions is tightly regulated through the balance between activating phosphorylation by upstream kinases and inactivating dephosphorylation by phosphatases. Disruption of homeostatic ERK1/2 regulation caused by elevated extracellular signals or mutations in upstream regulatory proteins leads to the constitutive activation of ERK1/2 signaling and uncontrolled cell proliferation observed in many types of cancer. Many inhibitors of upstream kinase regulators of ERK1/2 have been developed and are part of targeted therapeutic options to treat a variety of cancers. However, the efficacy of these drugs in providing sustained patient responses is limited by the development of acquired resistance often involving re-activation of ERK1/2. As such, recent drug discovery efforts have focused on the direct targeting of ERK1/2. Several ATP competitive ERK1/2 inhibitors have been identified and are being tested in cancer clinical trials. One drug, Ulixertinib (BVD-523), has received FDA approval for use in the Expanded Access Program for patients with no other therapeutic options. This review provides an update on ERK1/2 inhibitors in clinical trials, their successes and limitations, and new academic drug discovery efforts to modulate ERK1/2 signaling for treating cancer and other diseases.
Subject(s)
Neoplasms , Protein Kinase Inhibitors , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Animals , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Mitogen-Activated Protein Kinase 3/metabolism , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Drug Development , MAP Kinase Signaling System/drug effectsABSTRACT
The RAS-RAF-MEK-ERK signaling cascade is abnormally activated in various tumors, playing a crucial role in mediating tumor progression. As the key component at the terminal stage of this cascade, ERK1/2 emerges as a potential antitumor target and offers a promising therapeutic strategy for tumors harboring BRAF or RAS mutations. Here, we identified 36c with a (thiophen-3-yl)aminopyrimidine scaffold as a potent ERK1/2 inhibitor through structure-guided optimization for hit 18. In preclinical studies, 36c showed powerful ERK1/2 inhibitory activities (ERK1/2 IC50 = 0.11/0.08 nM) and potent antitumor efficacy both in vitro and in vivo against triple-negative breast cancer and colorectal cancer models harboring BRAF and RAS mutations. 36c could directly inhibit ERK1/2, significantly block the phosphorylation expression of their downstream substrates p90RSK and c-Myc, and induce cell apoptosis and incomplete autophagy-related cell death. Taken together, this work provides a promising ERK1/2 lead compound for multiple tumor-treatment drug discovery.
Subject(s)
Antineoplastic Agents , Protein Kinase Inhibitors , Pyrimidines , Humans , Pyrimidines/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Structure-Activity Relationship , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Thiophenes/pharmacology , Thiophenes/chemical synthesis , Thiophenes/chemistry , Mitogen-Activated Protein Kinase 3/metabolism , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Cell Line, Tumor , Drug Discovery , Apoptosis/drug effects , Female , Mice, Nude , Drug Screening Assays, Antitumor , Molecular Structure , Cell Proliferation/drug effects , Xenograft Model Antitumor Assays , Mice, Inbred BALB CABSTRACT
OBJECTIVE: This study aimed to investigate BVD-523 (ulixertinib), an adenosine triphosphate (ATP)-dependent extracellular signal-regulated kinases 1/2 inhibitor, for its antitumor potential in thyroid cancer. MATERIALS AND METHODS: Ten thyroid cancer cell lines known to carry mitogen-activated protein kinase (MAPK)-activated mutations, including v-Raf murine sarcoma viral oncogene homolog B (BRAF) and rat sarcoma virus (RAS) mutations, were examined. Cells were exposed to a 10-fold concentration gradient ranging from 0 to 3000 nM for 5 days. The half-inhibitory concentration was determined using the Cell Counting Kit-8 assay. Following BVD-523 treatment, cell cycle analysis was conducted using flow cytometry. In addition, the impact of BVD-523 on extracellular signal-regulated kinase (ERK)- dependent ribosomal S6 kinase (RSK) activation and the expression of cell cycle markers were assessed through western blot analysis. RESULTS: BVD-523 significantly inhibited thyroid cancer cell proliferation and induced G1/S cell cycle arrest dose-dependently. Notably, cell lines carrying MAPK mutations, especially those with the BRAF V600E mutation, exhibited heightened sensitivity to BVD-523's antitumor effects. Furthermore, BVD-523 suppressed cyclin D1 and phosphorylated retinoblastoma protein expression, and it robustly increased p27 levels in an RSK-independent manner. CONCLUSION: This study reveals the potent antitumor activity of BVD-523 against thyroid cancer cells bearing MAPK-activating mutations, offering promise for treating aggressive forms of thyroid cancer.
Subject(s)
Aminopyridines , Cell Proliferation , Pyrroles , Thyroid Neoplasms , Humans , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/pathology , Thyroid Neoplasms/genetics , Thyroid Neoplasms/metabolism , Cell Proliferation/drug effects , Cell Line, Tumor , Protein Kinase Inhibitors/pharmacology , Pteridines/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/metabolism , Mitogen-Activated Protein Kinase 3/genetics , Antineoplastic Agents/pharmacology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mutation , MAP Kinase Signaling System/drug effectsABSTRACT
Rotavirus (RV) is the main pathogen that causes severe diarrhea in infants and children under 5 years of age. No specific antiviral therapies or licensed anti-rotavirus drugs are available. It is crucial to develop effective and low-toxicity anti-rotavirus small-molecule drugs that act on novel host targets. In this study, a new anti-rotavirus compound was selected by ELISA, and cell activity was detected from 453 small-molecule compounds. The anti-RV effects and underlying mechanisms of the screened compounds were explored. In vitro experimental results showed that the small-molecule compound ML241 has a good effect on inhibiting rotavirus proliferation and has low cytotoxicity during the virus adsorption, cell entry, and replication stages. In addition to its in vitro effects, ML241 also exerted anti-RV effects in a suckling mouse model. Transcriptome sequencing was performed after adding ML241 to cells infected with RV. The results showed that ML241 inhibited the phosphorylation of ERK1/2 in the MAPK signaling pathway, thereby inhibiting IκBα, activating the NF-κB signaling pathway, and playing an anti-RV role. These results provide an experimental basis for specific anti-RV small-molecule compounds or compound combinations, which is beneficial for the development of anti-RV drugs.
Subject(s)
Antiviral Agents , Rotavirus Infections , Rotavirus , Virus Replication , Rotavirus/drug effects , Rotavirus/physiology , Animals , Mice , Rotavirus Infections/drug therapy , Rotavirus Infections/virology , Virus Replication/drug effects , Humans , Antiviral Agents/pharmacology , Mitogen-Activated Protein Kinase 3/metabolism , Mitogen-Activated Protein Kinase 3/genetics , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , NF-kappa B/metabolism , Phosphorylation , Mice, Inbred BALB C , Cell Line , MAP Kinase Signaling System/drug effects , Signal Transduction/drug effectsABSTRACT
No disponible
Subject(s)
Humans , Melanoma/pathology , Skin Neoplasms/pathology , Antineoplastic Agents/therapeutic use , Histocytological Preparation Techniques/methods , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Drug ApprovalABSTRACT
El melanoma ha experimentado un aumento constante en su tasa de incidencia en las últimas cinco décadas a nivel mundial. El pronóstico del paciente con melanoma se relaciona con el estadio de la enfermedad al momento del diagnóstico, con una sobrevida global media de 6,2 meses en pacientes con melanoma metastásico. El avance en las investigaciones sobre la biología y el comportamiento tumoral permitió el desarrollo de nuevas terapias con distintos mecanismos de acción y mayor eficacia. En esta revisión se abordan las terapias biológicas en melanoma metastásico, su mecanismo de acción y principales resultados en ensayos clínicos. (AU)
Melanoma has experienced a consistent increase in incidence over the past five decades worldwide. The prognosis of patients with melanoma is related to the stage of disease at diagnosis, with a median overall survival of 6.2 months in metastatic melanoma. Progress in research on tumor biology allowed the development of new therapies with different mechanisms of action and greater efficiency. In this review, biologic therapies in metastatic melanoma, its mechanism of action and main results in clinical trials are discussed. (AU)
Subject(s)
Humans , Biological Therapy , Melanoma/therapy , Neoplasm Metastasis/therapy , Incidence , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Dacarbazine/adverse effects , Dacarbazine/therapeutic use , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Ipilimumab/adverse effects , Ipilimumab/therapeutic use , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Vemurafenib/adverse effects , Vemurafenib/therapeutic use , Nivolumab/adverse effects , Nivolumab/therapeutic use , ImmunotherapyABSTRACT
OBJETIVO: Estimar a prevalência de dor crônica e sua associação com a situação socioeconômica, demográfica e atividade física no lazer em idosos. MÉTODOS: Este estudo é parte do inquérito epidemiológico e transversal de base populacional e domiciliar EpiFloripa Idoso 2009-2010 realizado com 1.705 idosos (≥ 60 anos), residentes em Florianópolis, Santa Catarina. A partir da resposta afirmativa de dor crônica, foram investigadas as associações com as variáveis obtidas por meio de entrevista estruturada. Realizou-se a estatística descritiva, incluindo cálculos de proporções e intervalos de confiança 95% (IC95%). Na análise bruta e ajustada, empregou-se regressão de Poisson, estimando-se as razões de prevalência, com intervalos de confiança de 95% e valores p ≤ 0,05. RESULTADOS: Dentre os idosos investigados, 29,3% (IC95% 26,5 - 32,2) relataram dor crônica. Na análise ajustada, observou-se que as variáveis sexo feminino, menor escolaridade e pior situação econômica ficaram associadas significativamente com maior prevalência de dor crônica; ser fisicamente ativo no lazer ficou associado significativamente com menor prevalência do desfecho. CONCLUSÕES: Percebe-se que a dor crônica é um agravo que acomete considerável parcela de idosos, havendo desigualdades sociais na sua frequência e sendo beneficamente afetada pela atividade física no lazer. É necessário que políticas públicas de saúde subsidiem programas multidisciplinares de controle da dor incluindo a prática regular de atividade física, voltada especificamente à promoção da saúde do idoso, evitando assim que a dor crônica comprometa a qualidade de vida desta população. .
OBJECTIVE: To estimate the prevalence of chronic pain and its association with socioeconomic and demographic status, and leisure physical activity in the elderly population. METHODS: This study is part of an epidemiological cross-sectional population-based household survey called EpiFloripa Elderly 2009-2010, which was conducted with 1,705 elderly individuals (≥ 60 years) residents of Florianópolis, Santa Catarina. From the positive response to chronic pain, the associations with the variables were investigated through a structured interview. Descriptive statistics were conducted, including ratio calculation and 95% confidence intervals. In crude and adjusted analysis, Poisson regression was utilized, estimating prevalence ratios, with 95% confidence intervals and ≤ 0.05 p-values. RESULTS: Among the subjects, 29.3% (IC95% 26.5 - 32.2) reported chronic pain. Adjusted analysis showed that being female, having less years of schooling, and being in worse economic situation were significantly associated with a higher prevalence of chronic pain. Being physically active during leisure time was significantly associated with lower prevalence of the outcome. CONCLUSIONS: Therefore, it is clear that chronic pain affects a considerable amount of elderly individuals. Social inequalities are a harmful influence in these individuals' quality of life, inasmuch as those inequalities increase the frequency with which chronic pain afflicts them. At the same time, physical activity during leisure time decreases chronic pain frequency. It is fundamental that public health policies subsidize multidisciplinary pain management programs, which should include health targeted physical activity for the elderly, thus preventing the decrease in quality of life that chronic pain brings to this population. .
Subject(s)
Animals , Humans , Early Growth Response Protein 1/genetics , Epithelial Cells/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , /metabolism , Sulindac/analogs & derivatives , Apoptosis/drug effects , Blotting, Western , Butadienes/pharmacology , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Early Growth Response Protein 1/metabolism , Epithelial Cells/cytology , Epithelial Cells/metabolism , Imidazoles/pharmacology , Intestines/cytology , Intestines/drug effects , Intestines/metabolism , Luciferases/genetics , Luciferases/metabolism , Microscopy, Confocal , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , /antagonists & inhibitors , Nitriles/pharmacology , Pyridines/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction/drug effects , Sulindac/pharmacology , Transfection , Up-Regulation/drug effects , ets-Domain Protein Elk-1/genetics , ets-Domain Protein Elk-1/metabolismABSTRACT
BACKGROUND/AIMS: We examined the effects of cilostazol on mitogen-activated protein kinase (MAPK) activity and its relationship with cilostazol-mediated protection against apoptosis in lipopolysaccharide (LPS)-treated endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to LPS and cilostazol with and without specific inhibitors of MAPKs; changes in MAPK activity in association with cell viability and apoptotic signaling were investigated. RESULTS: Cilostazol protected HUVECs against LPS-induced apoptosis by suppressing the mitochondrial permeability transition, cytosolic release of cytochrome c, and subsequent activation of caspases, stimulating extracellullar signal-regulated kinase (ERK1/2) and p38 MAPK signaling, and increasing phosphorylated cAMPresponsive element-binding protein (CREB) and Bcl-2 expression, while suppressing Bax expression. These cilostazol-mediated cellular events were effectively blocked by MAPK/ERK kinase (MEK1/2) and p38 MAPK inhibitors. CONCLUSIONS: Cilostazol protects HUVECs against LPS-induced apoptosis by suppressing mitochondriadependent apoptotic signaling. Activation of ERK1/2 and p38 MAPKs, and subsequent stimulation of CREB phosphorylation and Bcl-2 expression, may be responsible for the cellular signaling mechanism of cilostazolmediated protection.
Subject(s)
Humans , Apoptosis/drug effects , Caspases/metabolism , Cell Line , Cell Survival/drug effects , Cyclic AMP Response Element-Binding Protein/metabolism , Cytochromes c/metabolism , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , Lipopolysaccharides/toxicity , Mitochondrial Membrane Transport Proteins/drug effects , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacology , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction/drug effects , Tetrazoles/pharmacology , Time Factors , bcl-2-Associated X Protein/metabolism , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
Unmethylated CpG oligodeoxynucleotides (CpG ODNs) activate immune cells to produce immune mediators. This study demonstrates that in murine macrophage RAW 264.7 cells, CpG ODN-mediated matrix metalloproteinase-9 (MMP-9) expression is regulated at transcriptional level and requires de novo protein synthesis. Inhibition of ERK and p38 MAPK, but not JNK, results in significant decrease of CpG ODN-induced MMP-9 expression. We found that endosomal maturation inhibitors, chloroquine and bafilomycin A, block CpG ODN-induced ERK and p38 MAPK activation and the subsequent MMP-9 expression. We also observed that CpG ODN induces NF-kappa B activation and NF-kappa B is a downstream target of p38 MAPK. Taken together, our data demonstrate that CpG ODN triggers MMP-9 expression via TLR-9 dependent ERK and p38 MAPK activation followed by NF-kappa B activation.
Subject(s)
Animals , Mice , Cell Line , Enzyme Activation/drug effects , Enzyme Induction/drug effects , Matrix Metalloproteinase 9/biosynthesis , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Oligodeoxyribonucleotides/pharmacology , Signal Transduction/drug effects , Toll-Like Receptor 9/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
Angiotensin II (Ang II), which is an important mediator of both vascular responsiveness and growth, has been shown to induce vascular smooth muscle cell (VSMC) hypertrophy via the activation of a complex series of intracellular signaling events. Heat shock protein 70 (Hsp70) has recently been shown to protect against Ang II-induced hypertension. In this study, we tested the hypothesis that Hsp70 can protect VSMC from Ang II-induced hypertrophy. We treated VSMCs with Ang II to induce hypertrophy and to activate MAPK signaling pathway. We observed that the augmentation of Hsp70 expression inhibited Ang II-stimulated VSMC hypertrophy. This inhibitory effect of Hsp70 appears to be partly due to extracellular signal-regulated kinase (ERK1/2) inactivation, which in turn, may possibly result from the accumulation of MAP kinase phosphatase-1 (MKP-1).
Subject(s)
Rats , Male , Animals , Rats, Sprague-Dawley , RNA, Small Interfering/pharmacology , Protein Tyrosine Phosphatases/metabolism , Phosphoprotein Phosphatases/metabolism , Muscle, Smooth, Vascular/cytology , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/metabolism , MAP Kinase Kinase 1/metabolism , Immediate-Early Proteins/metabolism , Hypertrophy , HSP70 Heat-Shock Proteins/antagonists & inhibitors , Flavonoids/pharmacology , Enzyme Stability/drug effects , Cells, Cultured , Cell Cycle Proteins/metabolism , Aorta/drug effects , Angiotensin II/pharmacologyABSTRACT
Nitric oxide (NO) seems to play a pivotal role in the vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation. This study was designed to investigate the role and intracellular signal pathway of endothelial nitric oxide synthase (eNOS) activation induced by VEGF. ECV 304 cells were treated with betaVEGF(165) and then cell proliferation, eNOS protein and mRNA expression levels were analyzed to elucidate the functional role of eNOS in cell proliferation induced by VEGF. After exposure of cells to betaVEGF(165) , eNOS activity and cell growth were increased by approximately two-fold in the betaVEGF(165) -treated cells compared to the untreated cells. In addition, VEGF stimulated eNOS expression at both the mRNA and protein levels in a dose-dependent manner. Phosphatidylinositol-3 kinase (PI-3K) inhibitors were used to assess PI-3K involvement in eNOS regulation. LY294002 was found to attenuate VEGF-stimulated eNOS expression. Wortmannin was not as effective as LY294002, but the reduction effect was detectable. Cells activated by VEGF showed increased ERK1/2 levels. Moreover, the VEGF-induced eNOS expression was reduced by the PD98059, MAPK pathway inhibitor. This suggests that eNOS expression might be regulated by PI-3K and the ERK1/2 signaling pathway. In conclusion, betaVEGF(165) induces ECV 304 cell proliferation via the NO produced by eNOS. In addition, eNOS may be regulated by the PI-3K or mitogen-activated protein kinase pathway.