Glioblastoma (GBM) is a brain tumor characterized by poor therapeutic response and overall survival. Despite relevant progress in conventional treatments represented by the clinical use of temozolomide (TMZ), a combination of approaches might be a possible future direc-tion for treating GBM. Transforming growth factor-beta-activated kinase-1 (TAK1) is an essential component in genotoxic stresses-induced NF-κB-activation and mitogen-activated protein kinase (MAPK)-pathways; however, the role of TAK1 in GBM-chemoresistance remains unknown. This study aimed to verify, in GBM human cell lines, in an in vivo U87-xenograft model and in TMZ-treated-patients, the effect of TAK1 inhibition on the sensitivity of GBM cells to chemotherapy. In vitro model, using GBM cell lines, showed that 5Z-7-oxozeaenol augmented the cytotoxic effects of TMZ, blocking TMZ-induced NF-κB-activation, reducing DNA-damage and enhancing TMZ-induced apoptosis in GMB cell lines. We showed a reduction in tumor burden as well as tumor volume in the xenograft model following the treatment with 5Z-7-oxozaenol associated with TMZ. Our results showed a significant up-regulation in TAK1, p-p38, p-JNK and NF-κB in glioblastoma TMZ-treated-patients and denoted the role of 5Z-7-oxozeaenol in increasing the sensitivity of GBM cells to chemotherapy, proving to be an effective coadjuvant to current GBM chemotherapeutic regimens, suggesting a new option for therapeutic treatment of GBM.

TAK1 inhibitor enhances the therapeutic treatment for glioblastoma

Campolo M.;Lanza M.;Casili G.;Paterniti I.;Filippone A.;Caffo M.;Cardali S. M.;Puliafito I.;Raciti G.;Cuzzocrea S.;Esposito E.
2021

Abstract

Glioblastoma (GBM) is a brain tumor characterized by poor therapeutic response and overall survival. Despite relevant progress in conventional treatments represented by the clinical use of temozolomide (TMZ), a combination of approaches might be a possible future direc-tion for treating GBM. Transforming growth factor-beta-activated kinase-1 (TAK1) is an essential component in genotoxic stresses-induced NF-κB-activation and mitogen-activated protein kinase (MAPK)-pathways; however, the role of TAK1 in GBM-chemoresistance remains unknown. This study aimed to verify, in GBM human cell lines, in an in vivo U87-xenograft model and in TMZ-treated-patients, the effect of TAK1 inhibition on the sensitivity of GBM cells to chemotherapy. In vitro model, using GBM cell lines, showed that 5Z-7-oxozeaenol augmented the cytotoxic effects of TMZ, blocking TMZ-induced NF-κB-activation, reducing DNA-damage and enhancing TMZ-induced apoptosis in GMB cell lines. We showed a reduction in tumor burden as well as tumor volume in the xenograft model following the treatment with 5Z-7-oxozaenol associated with TMZ. Our results showed a significant up-regulation in TAK1, p-p38, p-JNK and NF-κB in glioblastoma TMZ-treated-patients and denoted the role of 5Z-7-oxozeaenol in increasing the sensitivity of GBM cells to chemotherapy, proving to be an effective coadjuvant to current GBM chemotherapeutic regimens, suggesting a new option for therapeutic treatment of GBM.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11570/3184362
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