RESUMEN
The receptor tyrosine kinase AXL (RTK-AXL) is implicated in therapy resistance and tumor progression in glioblastoma multiforme (GBM). Here, we investigated therapy-induced receptor modifications and how endogenous RTK-AXL expression and RTK-AXL inhibition contribute to therapy resistance in GBM. GBM cell lines U118MG and SF126 were exposed to temozolomide (TMZ) and radiation (RTX). Receptor modifications in response to therapy were investigated on protein and mRNA levels. TMZ-resistant and RTK-AXL overexpressing cell lines were exposed to increasing doses of TMZ and RTX, with and without RTK-AXL tyrosine kinase inhibitor (TKI). Colorimetric microtiter (MTT) assay and colony formation assay (CFA) were used to assess cell viability. Results showed that the RTK-AXL shedding product, C-terminal AXL (CT-AXL), rises in response to repeated TMZ doses and under hypoxia, acts as a surrogate marker for radio-resistance. Endogenous RTX-AXL overexpression leads to therapy resistance, whereas combination therapy of TZM and RTX with TKI R428 significantly increases therapeutic effects. This data proves the role of RTK-AXL in acquired and intrinsic therapy resistance. By demonstrating that therapy resistance may be overcome by combining AXL TKI with standard treatments, we have provided a rationale for future study designs investigating AXL TKIs in GBM.
Asunto(s)
Benzocicloheptenos/farmacología , Neoplasias Encefálicas/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Glioblastoma/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Temozolomida/farmacología , Triazoles/farmacología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Terapia Combinada , Resistencia a Antineoplásicos/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Glioblastoma/metabolismo , Glioblastoma/terapia , Humanos , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Hipoxia Tumoral/efectos de los fármacos , Hipoxia Tumoral/efectos de la radiación , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/efectos de la radiación , Tirosina Quinasa del Receptor AxlRESUMEN
The packaging of fresh meat has been studied for decades, leading to improved packaging types and conditions such as modified atmosphere packaging (MAP). While commonly used meat packaging uses fossil fuel-based materials, the use of biodegradable packaging materials for this application has not been studied widely. This study aimed at evaluating the sustainability of biodegradable packaging materials compared to established conventional packaging materials through analyses of the quality of freshly packaged pork. The quality was assessed by evaluating sensory aspects, meat color and microbiological attributes of the pork products. The results show no significant differences (p > 0.05) in ground pork and pork loin stored in biodegradable MAP (BioMAP) and conventional MAP for the evaluated sensory attributes, meat color or total bacterial count (TBC) over extended storage times. The data suggest that BioMAP could be a viable alternative to MAP using conventional, fossil fuel-based materials for the storage of fresh meats, while simultaneously fulfilling the customers' wishes for a more environmentally friendly packaging alternative.