title: Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression.
abstract: The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC50) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN.
authors.affiliation: Department of Radiation Oncology, Tianjin Hospital, Tianjin, P.R. China.
authors.forename: Fengming
authors.initials: F
authors.lastname: Lan
authors.affiliation: Department of Orthopedics, Tianjin Hospital, Tianjin, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, The Fifth Central Hospital of Tianjin, Tianjin, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.affiliation: Tianjin Huanhu Hospital, Tianjin Neurosurgery Institute, Tianjin, P.R. China.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research, Department of Radiotherapy, Peking University Cancer Hospital, Beijing, P.R. China.
authors.forename: Huiming
authors.initials: H
authors.lastname: Yu
authors.affiliation: Tianjin Huanhu Hospital, Tianjin Neurosurgery Institute, Tianjin, P.R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yue
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013454:Sulfoxides; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D017879:Isothiocyanates; D016328:NF-kappa B; D013454:Sulfoxides; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; C016766:sulforaphane; D000077204:Temozolomide