knk-437 and Glioblastoma

Previous study indicated that PS-341 induces cell death via JNK pathway in vitro in glioma. However, suppressing proteasome complex by PS-341 may induce expression of heat shock proteins (HSPs), which confer potential protection against cellular stress. In this study, we explored whether induction of HSPs could impair PS-341-induced cell death and whether inhibition of HSPs could enhance cell damage induced by PS-341 in glioma cells.. HSP expression in glioma cells was modulated by HSP inhibitor, sublethal heat, or knockdown of heat shock factor1 (HSF1), then PS-341-induced cell damage was examined by different methods. Similar experiments were also performed in HSF1+/+ and HSF1-/- cells. HSP70 expression and HSF1 nuclear localization were compared between glioma and normal brain tissues.. HSP level was upregulated mediated by HSF1 when glioma cells were treated with PS-341. PS-341-mediated cell damage could be significantly augmented by HSP inhibition. Furthermore, HSP70 expression and HSF1 nuclear localization were much more abundant in gliomas than in normal brain tissues.. Our results demonstrated that HSP70 impaired cell death induced by PS-341 in glioma cells. Administration of PS-341 in combination with either HSP70 inhibitor or HSF1 knockdown may act as a new approach to treatment of glioma.

Topics: Antineoplastic Agents; Apoptosis; Benzhydryl Compounds; Boronic Acids; Bortezomib; Brain; Cell Line, Tumor; Cell Nucleus; DNA-Binding Proteins; Gene Knockdown Techniques; Glioblastoma; Heat Shock Transcription Factors; Hot Temperature; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; JNK Mitogen-Activated Protein Kinases; Phosphorylation; Pyrazines; Pyrrolidinones; RNA, Small Interfering; Transcription Factors; Up-Regulation

We examined the effects of a heat shock protein (hsp) inhibitor, N-formyl-3, 4-methylenedioxy-gamma-butyrolactam (KNK437), on the radiosensitivity of human glioblastoma cells (A-172).. Effects of KNK437 on radiosensitivity and cell cycle regulation were examined using colony formation assays, flow cytometry analysis and Western blot analysis. KNK437 was added to the culture medium 1 h before X-ray irradiation at 50, 100 or 300 microM final concentration.. KNK437 induced the resistance of A-172 cells and human squamous cell carcinoma cells (SAS) to X-rays. Flow cytometry analysis showed that KNK437 alone efficiently induced A-172 cells to enter G2/M phase. Though A-172 cells irradiated with X-rays at 6 Gy showed no clear change in the cell cycle, the irradiated cells were induced to enter G2/M phase when they had been pre-treated with KNK437. By Western blot analysis, p53, 14-3-3sigma and cell division cycle 2 (cdc2) proteins that function in G2 arrest were observed to be persistently accumulated or phosphorylated in KNK437-treated cells, regardless of X-ray irradiation.. These results show that KNK437 causes cells to be resistant to radiation, and that this might be correlated with maintenance of G2 arrest in the cell cycle regulation.

Topics: Benzhydryl Compounds; Cell Cycle; Cell Line; Cell Survival; Dose-Response Relationship, Radiation; Glioblastoma; Heat-Shock Proteins; Humans; Pyrrolidinones; Radiation Tolerance