RESUMEN
The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKß independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.
Asunto(s)
Viroterapia Oncolítica , Virus Oncolíticos , Succinatos , Animales , Humanos , Viroterapia Oncolítica/métodos , Succinatos/farmacología , Ratones , Línea Celular Tumoral , Interferón Tipo I/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias del Colon/terapia , Neoplasias del Colon/inmunología , Neoplasias del Colon/tratamiento farmacológico , Antivirales/farmacología , FN-kappa B/metabolismo , Quinasa I-kappa B/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Inflamación/tratamiento farmacológico , Femenino , Virus de la Estomatitis Vesicular Indiana/fisiología , Virus de la Estomatitis Vesicular Indiana/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
DNA is a danger signal sensed by cGAS to engage signaling through STING to activate innate immune functions. The best-studied downstream responses to STING activation include expression of type I interferon and inflammatory genes, but STING also activates other pathways, including apoptosis. Here, we report that STING-dependent induction of apoptosis in macrophages occurs through the intrinsic mitochondrial pathway and is mediated via IRF3 but acts independently of gene transcription. By intersecting four mass spectrometry datasets, we identify SAM68 as crucial for the induction of apoptosis downstream of STING activation. SAM68 is essential for the full activation of apoptosis. Still, it is not required for STING-mediated activation of IFN expression or activation of NF-κB. Mechanistic studies reveal that protein trafficking is required and involves SAM68 recruitment to STING upon activation, with the two proteins associating at the Golgi or a post-Golgi compartment. Collectively, our work identifies SAM68 as a STING-interacting protein enabling induction of apoptosis through this DNA-activated innate immune pathway.
Asunto(s)
Proteínas de la Membrana , Transducción de Señal , Proteínas de la Membrana/metabolismo , Macrófagos/metabolismo , Proteínas de Ciclo Celular/metabolismo , ADN/metabolismo , ApoptosisRESUMEN
Adjusting the protecting group strategy, from an alkyl ether to a bidentate ketal at the carbohydrate backbone of uridine, facilitates a switchable diastereoselective α- or ß-C4'/C5'-spirocyclopropanation. Using these spirocyclopropanated nucleosides as key intermediates, we synthesized a variety of C4'-methylated d-ribose and l-lyxose-configured uridine derivatives by a base-mediated ring-opening of the spirocyclopropanol moiety. Investigations of antiviral activity against the human respiratory syncytial virus were carried out for selected derivatives, showing moderate activity.
Asunto(s)
Virus Sincitial Respiratorio Humano , Antivirales/farmacología , Humanos , Nucleósidos , Uridina/farmacologíaRESUMEN
The Simmons-Smith-Furukawa reaction was used to generate 4'/5'-spirocyclopropanated uridine analogs from electron-rich exocyclic enol esters. During synthesis, the native hydroxylation pattern of the nucleoside is preserved and offers the possibility for a late stage 5'-phosphorylation at the spirocyclopropanol moiety. All synthesized spirocyclopropanated uridine derivatives, including the corresponding 5'-monophosphate (cpUMP), were evaluated with respect to their antiviral activity in an HRSV assay showing moderate, but promising activity.
Asunto(s)
Antivirales/farmacología , Ciclopropanos/farmacología , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Compuestos de Espiro/farmacología , Uridina/farmacología , Antivirales/síntesis química , Antivirales/química , Cristalografía por Rayos X , Ciclopropanos/síntesis química , Ciclopropanos/química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Uridina/análogos & derivados , Uridina/síntesis químicaRESUMEN
C5/C6-Spirocyclopropanation of exocyclic enol esters followed by alkali ring-opening of the three-membered ring was used for the diastereoselective preparation of 5-C-methylated d-mannose, d-galactose, l-gulose, and l-altrose. Extensive NMR studies demonstrated an increase of furanose form by 5-C-methylation in almost all cases.