Abstract
BackgroundThe primary glioblastoma multiforme (GBM) is the most malignant form of astrocytic tumor with an average survival of approximately 12–14 months. The search for novel and more efficient chemo-agents against this disease is urgent. Salinomycin induces broad anti-cancer effects; however, its role in GBM and the underlying mechanism are not clear.ResultsHere we found that salinomycin induced both apoptosis and necrosis in cultured glioma cells, and necrosis played a major role in contributing salinomycin’s cytotoxicity. Salinomycin induced p53 translocation to mitochondria, where it formed a complex with cyclophilin-D (CyPD). This complexation was required for mitochondrial permeability transition pore (mPTP) opening and subsequent programmed necrosis. Blockade of Cyp-D by siRNA-mediated depletion or pharmacological inhibitors (cyclosporin A and sanglifehrin A) significantly suppressed salinomycin-induced glioma cell necrosis. Meanwhile, p53 stable knockdown alleviated salinomycin-induced necrosis in glioma cells. Reactive oxygen species (ROS) production was required for salinomycin-induced p53 mitochondrial translocation, mPTP opening and necrosis, and anti-oxidants n-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) inhibited p53 translocation, mPTP opening and glioma cell death.ConclusionsThus, salinomycin mainly induces programmed necrosis in cultured glioma cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0174-1) contains supplementary material, which is available to authorized users.
Highlights
The primary glioblastoma multiforme (GBM) is the most malignant form of astrocytic tumor with an average survival of approximately 12–14 months
We found that salinomycin induced programmed necrosis in cultured glioma cells
Using the trypan blue staining assay, we found that salinomycin treatment caused significant cytotoxicity of U87MG cell death, and the effect again was dose-dependently (Fig. 1c)
Summary
The primary glioblastoma multiforme (GBM) is the most malignant form of astrocytic tumor with an average survival of approximately 12–14 months. The search for novel and more efficient chemo-agents against this disease is urgent. Salinomycin induces broad anti-cancer effects; its role in GBM and the underlying mechanism are not clear. The primary glioblastoma multiforme (GBM) is the most malignant form of astrocytic tumor, which has one of the worst prognoses among all human tumors, with a median survival of approximately 12 months [1,2,3,4,5,6,7]. The search for novel and more efficient chemo-agents against this deadly disease is urgent and important [2]. We investigated the potential role of salinomycin in glioma cells, and studied the molecular mechanisms involved
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