Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival

Abstract

The survival for patients with high-grade glioma is poor, and only a limited number of patients respond to the therapy. The aim of this study was to analyze the significance of using p38 MAPK phosphorylation as a prognostic marker in high-grade glioma patients and as a therapeutic target in combination chemotherapy with vandetanib. p38 MAPK phosphorylation was analyzed with immunohistochemistry in 90 high-grade glioma patients. Correlation between p38 MAPK phosphorylation and overall survival was analyzed with Mann-Whitney U test analysis. The effects on survival of glioblastoma cells of combining vandetanib with the p38 MAPK inhibitor SB 203580 were analyzed in vitro with the median-effect method with the fluorometric microculture cytotoxicity assay. Two patients had phosphorylated p38 MAPK in both the cytoplasm and nucleus, and these two presented with worse survival than patients with no detectable p38 MAPK phosphorylation or phosphorylated p38 MAPK only in the nucleus. This was true for both high-grade glioma patients (WHO grade III and IV, n = 90, difference in median survival: 6.1 months, 95 % CI [0.20, 23], p = 0.039) and for the subgroup with glioblastoma patients (WHO grade IV, n = 70, difference in median survival: 6.1 months, 95 % CI [0.066, 23], p = 0.043). The combination of vandetanib and the p38 MAPK inhibitor SB 203580 had synergistic effects on cell survival for glioblastoma-derived cells in vitro. In conclusion, p38 MAPK phosphorylation may be a prognostic marker for high-grade glioma patients, and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for glioma patients.

Cytocidal effects of arenobufagin and hellebrigenin, two active bufadienolide compounds, against human glioblastoma cell line U-87

“…Increasing evidence has indicated an important role for the PI3K/Akt signaling pathway in the regulation of cell survival and death in response to diverse stimuli, including the majority of chemotherapeutic agents ( 46 , 47 ). In addition, members of the MAPK family, consisting of p38, Erk and JNK, are also involved in a range of cellular functions, including proliferation, cell cycle arrest and cell death ( 26 , 27 , 48 , 49 ). In the present study, evident activation of p38 MAPK pathway was observed in U-87 cells when treated with arenobufagin or hellebrigenin as evidenced by a marked increase in the expression levels of phospho-p38 and its direct downstream target, phospho-MK2 ( 25 ).…”

“…In agreement with these findings, previous studies have demonstrated a pro-survival role for p38 MAPK in different types of cells, including human glioblastoma cells ( 48 , 50 ). Sooman et al ( 27 ) reported that p38 MAPK phosphorylation may be a prognostic marker for patients with high-grade glioma, and vandetanib combined with a p38 MAPK inhibitor may be a useful combination chemotherapy for patients with glioma. Considering the results of previous studies and the observations in the present study, we hypothesized that combining a p38 MAPK inhibitor with arenobufagin or hellebrigenin may improve the efficacy of both drugs, and may provide more therapeutic benefits to patients with glioblastoma, although the precise contribution of the p38 MAPK pathway to the cytotoxicity of the two drugs warrants further investigation in a glioblastoma xenograft model.…”

“…Similar to Akt, Erk is usually referred to as a survival mediator involved in cytoprotection ( 21 , 22 ). Although p38 MAPK and JNK are generally considered to be required for the induction of cell death by diverse stimuli ( 21 , 23 , 24 ), a novel prosurvival role for p38 MAPK has been reported in human cancer cells, including in glioblastoma cells ( 25 - 27 ). However, whether and how these molecules contribute to the potential cytotoxic effects induced by active bufadienolides against glioblastoma cells, and the association between these molecules and cellular responses, including cell cycle arrest, remain to be elucidated.…”

Growth factors and kinases in glioblastoma growth

“…As such, combining different therapies is important to block alternative pathways and improve overall patient survival rates [103] . In view of all the different actions and interactions related to MAPK, its activation by phosphorylation has been proposed to be a prognostic marker [105,106] , particularly owing to the strong correlation between phosphorylated MAPK (pMAPK), proliferation, and resistance. Interestingly, the role of MAPK may be important not only because of its relationship with GBM cells but also because of its niched role in producing an inflammatory environment.…”

“…A previous study indicated that p38 MAPK blockage suppresses inflammatory response of GBM cells as well as IL-6 and IL-8 production, and this inflammatory condition promotes invasiveness, probably through MMP activation [107] . VEGFR has also been linked to invasiveness and migration, and a study on the combined inhibition of MAPK and VEGFR indicated that the blockage of both pathways increases survival [105] , once again emphasizing the importance of multiple targeting to inhibit several GBM processes.…”