title: TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy.
abstract: Treatment failure in high risk neuroblastoma is largely due to development of chemoresistance. 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 neuroblastoma remains unknown. Using a panel of neuroblastoma cell lines, we found that TAK1 inhibitor 5Z-7-oxozeaenol significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) on neuroblastoma cell lines. TAK1 inhibition also enhanced the inhibitory effect of Dox and VP-16 on anchorage-independent growth. Treatment of neuroblastoma cells with 5Z-7-oxozeaenol blocked Dox- and VP16-induced NF-κB activation and enhanced Dox- and VP16-induced apoptosis. Moreover, 5Z-7-oxozeaenol was able to overcome the established chemoresistance in LA-N-6 neuroblastoma cells. Using an orthotopic neuroblastoma mouse model, we found that 5Z-7-oxozeaenol significantly enhanced chemotherapeutic efficacy in vivo. Together, our results provide a proof-of-concept that TAK1 inhibition significantly increases the sensitivity of neuroblastoma cells to chemotherapy-induced cell-death and can serve as an effective adjunct to current chemotherapeutic regimens for high risk diseases.
authors.affiliation: Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Yihui
authors.initials: Y
authors.lastname: Fan
authors.forename: Jin
authors.initials: J
authors.lastname: Cheng
authors.forename: Sanjeev A
authors.initials: SA
authors.lastname: Vasudevan
authors.forename: Roma H
authors.initials: RH
authors.lastname: Patel
authors.forename: Li
authors.initials: L
authors.lastname: Liang
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.forename: Fengmin
authors.initials: F
authors.lastname: Lu
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Jed G
authors.initials: JG
authors.lastname: Nuchtern
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Kim
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D064593:Heterografts; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000008:administration & dosage; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D005047:Etoposide; D020930:MAP Kinase Kinase Kinases; D015025:Zearalenone; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols