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TAK1 Inhibitor 5Z‐7‐oxozeaenol Sensitizes Glioblastoma to Chemotherapy
Author(s) -
Casili Giovanna,
Campolo Michela,
Lanza Marika,
Filippone Alessia,
Cuzzocrea Salvatore,
Esposito Emanuela
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.835.5
Subject(s) - temozolomide , cancer research , apoptosis , mapk/erk pathway , chemotherapy , programmed cell death , cell culture , cell growth , cisplatin , p38 mitogen activated protein kinases , medicine , cancer , cell , chemistry , glioblastoma , biology , kinase , microbiology and biotechnology , biochemistry , genetics
Glioblastoma (GBM) are the most common and aggressive primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. NF‐κB activation is one of the resistance mechanisms for cancer cells to escape from chemotherapy‐induced cell‐death. TAK1 is an essential component in genotoxic stresses‐induced NF‐κB activation; however, the role of TAK1 in the development of chemoresistance in GBM remains unknown. The aim of the present study was to verify, in GBM human cell lines U138 and A172, if TAK1 inhibition significantly enhances the sensitivity of GBM cells to chemotherapy treatments. Also, to confirm the translationality of the study, GBM patients samples were used. Using GBM cell lines, U138 and A172, we found that TAK1 inhibitor 5Z‐7‐oxozeaenol significantly augmented the cytotoxic effects of temozolomide (TMZ). TAK1 inhibition also enhanced the inhibitory effect of TMZ on anchorage independent growth. Moreover, treatment of GBM cells with 5Z‐7‐oxozeaenol blocked TMZ‐ induced NF‐κB activation, reduced cytokines expression and enhanced TMZ‐induced apoptosis in both cell lines. Moreover, since MAPK are involved in the activation of NF‐κB, we investigated the MAPK role in GBM patients tissue, suggesting an effective role of MAPK in GBM modulation, highlighted by an up‐regulation of p‐p38 and pJNK in GBM patients samples. Together, our results provide a proof‐of‐concept that TAK1 inhibition significantly increases the sensitivity of GBM cells to chemotherapy‐induced cell‐death and can serve as an effective adjunct to current chemotherapeutic regimens for high‐risk diseases. Support or Funding Information No funding This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .