RESUMO
On-target-off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window of drug candidates1,2. In diseases of the central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition of mammalian target of rapamycin (mTOR) while sparing mTOR activity elsewhere through the use of the brain-permeable mTOR inhibitor RapaLink-1 and the brain-impermeable FKBP12 ligand RapaBlock. We show that this drug combination mitigates the systemic effects of mTOR inhibitors but retains the efficacy of RapaLink-1 in glioblastoma xenografts. We further present a general method to design cell-permeable, FKBP12-dependent kinase inhibitors from known drug scaffolds. These inhibitors are sensitive to deactivation by RapaBlock, enabling the brain-restricted inhibition of their respective kinase targets.
Assuntos
Encéfalo , Inibidores de MTOR , Sirolimo , Serina-Treonina Quinases TOR , Humanos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Quimioterapia Combinada , Glioblastoma/tratamento farmacológico , Ligantes , Inibidores de MTOR/metabolismo , Inibidores de MTOR/farmacocinética , Inibidores de MTOR/farmacologia , Sirolimo/análogos & derivados , Proteína 1A de Ligação a Tacrolimo/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A new class of poly(aryl ether) dendritic ligands containing a pyridine functionality at the focal point and the corresponding Ag(I) complexes through metal-ligand coordination were designed, synthesized, and fully characterized. Compared with the dendritic ligands, the corresponding dendritic complexes exhibited much better gelation ability for various organic solvents at very low critical gelation concentrations. The gel-sol phase transition temperatures and morphologies could be finely tuned by binding silver ion to the ligand. A preliminary study revealed that multiple noncovalent interactions, such as Ag(I) -pyridine coordination, solvophobic interaction, and π-π stacking, synergistically enable the formation of stable metallogels. Interestingly, these metallogels could intelligently respond to multiple external stimuli including temperature, chemicals, and shear stress, leading to gel-sol phase transitions. In addition, these dendritic metallogels were successfully applied as templates for the in situ formation and stabilization of silver nanoparticles without the use of any chemical reducing/stabilizing agents.
RESUMO
In this issue, Pine and colleagues compared single-cell RNA-sequencing data across four distinct types of glioblastoma stem cell-derived tumor models, reinforcing the importance of a three-dimensional microenvironment for accurate recapitulation of cellular states.See related article by Pine et al., p. 964.
Assuntos
Glioblastoma , Glioblastoma/genética , Humanos , Células-Tronco Neoplásicas , Microambiente TumoralRESUMO
The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting mTOR as a robust target for therapy. Inhibitors of mTOR have had limited success clinically, however, in part because their mechanism of action is cytostatic rather than cytotoxic. Here, we tested three distinct mTOR kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation of glioblastoma cells, whereas PP242 uniquely induced apoptosis. Apoptosis induced by PP242 resulted from off-target cooperative inhibition of JAK2 and protein kinase C alpha (PKCα). Induction of apoptosis was also decreased by additional on-target inhibition of mTOR, due to induction of autophagy. As EGFR inhibitors can block PKCα, EGFR inhibitors erlotinib and osimertinib were tested separately in combination with the JAK2 inhibitor AZD1480. Combination therapy induced apoptosis of glioblastoma tumors in both flank and in patient-derived orthotopic xenograft models, providing a preclinical rationale to test analogous combinations in patients. SIGNIFICANCE: These findings identify PKCα and JAK2 as targets that drive apoptosis in glioblastoma, potentially representing a clinically translatable approach for glioblastoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Feminino , Glioblastoma/patologia , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Camundongos , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Proteína Quinase C-alfa/antagonistas & inibidores , Proteína Quinase C-alfa/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/farmacologia , Purinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The transcription factor signal transducer and activator of transcription 3 (STAT3) drives progression in glioblastoma (GBM), suggesting STAT3 as a therapeutic target. Surprisingly however, GBM cells generally show primary resistance to STAT3 blockade. METHODS: Human glioblastoma cell lines LN229, U87, SF767, and U373, and patient-derived xenografts (PDXs) GBM8 and GBM43 were used to evaluate epidermal growth factor receptor (EGFR) activation during STAT3 inhibition. Protein and gene expression experiments, protein stability assays, cytokine arrays, phospho-tyrosine arrays and EGFR-ligand protein arrays were performed on STAT3 inhibitor-treated cells. To evaluate antitumor activity, we administered a betacellulin (BTC)-neutralizing antibody alone and in combination with STAT3 inhibition. BTC is an EGFR ligand. We therefore treated mice with orthotopic xenografts using the third-generation EGFR inhibitor osimertinib, with or without STAT3 knockdown. RESULTS: We demonstrate that both small-molecule inhibitors and knockdown of STAT3 led to expression and secretion of the EGFR ligand BTC, resulting in activation of EGFR and subsequent downstream phosphorylation of nuclear factor-kappaB (NF-κB). Neutralizing antibody against BTC abrogated activation of both EGFR and NF-κB in response to inhibition of STAT3; with combinatorial blockade of STAT3 and BTC inducing apoptosis in GBM cells. Blocking EGFR and STAT3 together inhibited tumor growth, improving survival in mice bearing orthotopic GBM PDXs in vivo. CONCLUSION: These data reveal a feedback loop among STAT3, EGFR, and NF-κB that mediates primary resistance to STAT3 blockade and suggest strategies for therapeutic intervention.
Assuntos
Glioblastoma , Animais , Betacelulina , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Camundongos , NF-kappa B/metabolismo , Fosforilação , Fator de Transcrição STAT3/metabolismoRESUMO
OBJECTIVE: The aim of this study was to conduct a meta-analysis of retrospective studies that investigated the association of preoperative C-reactive protein (CRP) levels with the overall survival (OS) of patients with bone neoplasms. METHODS: A detailed literature search was performed in the Cochrane Library, Web of Science, Embase and PubMed databases up to August 28, 2017, for related research publications written in English. We extracted the data from these studies and combined the hazard ratios (HR) and 95% confidence intervals (CIs) to assess the correlation between CRP levels and OS in patients with bone neoplasms. RESULTS: Five studies with a total of 816 participants from several countries were enrolled in this current meta-analysis. In a pooled analysis of all the publications, increased serum CRP levels had an adverse prognostic effect on the overall survival of patients with bone neoplasms. However, the combined data showed no significant relationship between the level of CRP and OS in Asian patients (HR = 1.73; 95% CI: 0.86-3.49; P = 0.125). Similar trends were observed in patients with bone neoplasms when stratified by ethnicity, histology, metastasis and study sample size. CONCLUSIONS: The results of this meta-analysis suggest that increased CRP expression indicates a poorer prognosis in patients with bone neoplasms. More prospective studies are needed to confirm the prognostic significance of CRP levels in patients with bone neoplasms.
Assuntos
Biomarcadores Tumorais , Neoplasias Ósseas/sangue , Neoplasias Ósseas/mortalidade , Proteína C-Reativa , Neoplasias Ósseas/cirurgia , Humanos , Período Pré-Operatório , Prognóstico , Modelos de Riscos Proporcionais , Viés de Publicação , Estudos RetrospectivosRESUMO
In this study, we demonstrated a highly sensitive electrochemical sensor for the determination of bisphenol A (BPA) in aqueous solution by using single-walled carbon nanotubes (SWCNTs)/ß-cyclodextrin (ß-CD) conjugate (SWCNT-CD) modified glassy carbon electrode (GCE). The cyclic voltammetry results show that the modified GCE exhibits strong catalytic activity toward the oxidation of BPA with a well-defined cyclic voltammetric peak at 0.543 V. The response current exhibits a linear range between 10.8 nM and 18.5 µM with a high sensitivity (1256 µA mM(-1)). The detection limit of BPA is 1.0 nM (S/N=3). The enhanced performance of the fabricated sensor can be attributed to the combination of the excellent electrocatalytic properties of SWCNTs and the molecular recognition ability of ß-CD. The sensor was successfully applied to determine BPA leached from real plastic samples with good recovery, ranging from 95% to 103%.