RESUMEN
Drug resistance has become a challenge in effective longterm molecular targeted therapy. Longterm non-small cell lung cancer (NSCLC) treatments with the first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) shorten the effective duration of the third-generation EGFR-TKI, osimertinib, via genetic or epigenetic mechanisms in addition to the gatekeeper mutation T790M. This study reproduced this persistence in vitro using gefitinib-resistant NSCLC PC-9 cells (GR cells) and revealed that pharmacological nuclear localization inhibition of ß-catenin suppressed the osimertinib resistance. Osimertinib effectively reduced GR cell survival but left significantly more resistant colonies than parental PC-9 cells. The nuclear fraction of ß-catenin was enriched in GR cells during acquisition of osimertinib resistance. A chemical nuclear localization inhibitor of ß-catenin, IMU1003, dramatically decreased the emergence of osimertinib-resistant colonies. Forced nuclear localization of ß-catenin reduced IMU1003 efficacy. Thus, suppression of the nuclear ß-catenin function may overcome the transgenerational EGFR-TKI-resistance.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Gefitinib/farmacología , Gefitinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genética , beta Catenina/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Resistencia a Antineoplásicos , Mutación , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéuticoRESUMEN
Aberrant activation of the canonical Wnt/ß-catenin signaling pathway triggers tumorigenesis in various tissues. This study identified an atrarate compound, IMU14, derived from filamentous fungi as an inhibitor of Wnt/ß-catenin signaling in phenotypic chemical inhibitor screening of the zebrafish eyeless phenotype. Its derivatization resulted in synthesis of IMU1003 with enhanced Wnt inhibitory activity. IMU1003 inhibited ß-catenin/TCF-dependent transcriptional activation and decreased nuclear ß-catenin level. In addition, IMU1003 selectively decreased viability and target gene products of the Wnt/ß-catenin signaling pathway in human non-colorectal cancer cell lines harboring intact APC and ß-catenin. Therefore, atrarate derivatives inhibit Wnt/ß-catenin signaling and show anticancer potential, and we developed a new class of chemical backbones for Wnt/ß-catenin signaling inhibitors.
Asunto(s)
Hidroxibenzoatos/farmacología , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismo , Animales , Animales Modificados Genéticamente , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Mutación , Vía de Señalización Wnt/genética , Pez Cebra/embriología , Pez Cebra/genéticaRESUMEN
Base-induced intramolecular cyclization of novel (4-aryl-2,4-dioxobutyl)methylphenylsulfonium salts prepared from the commercially available 1-arylethanone by a cost-effective process is described in this paper. The reaction was completed within 10 min to produce a family of 2-unsubstituted 5-aryl-3(2 H)-furanones in excellent yield. This procedure is simple, and can be carried out under mild conditions and an ambient atmosphere.
