Inhibition of MAPK/ERK, PKC and CaMKII Signaling Blocks Cytolysin-induced Human Glioma Cell Death

Background: Cytolysins are pore-forming toxins that show anticancer activity by a mechanism hitherto poorly investigated. Materials and Methods: To investigate how cytolysins are cytotoxic to resistant cancer cells, proliferation and cell death were evaluated on (187 glioblastoma cells treated with toxin Bc2 or equinatoxin-II (EqTx-II). Results: Toxins Bc2 and EqTx-II decreased cell viability and increased lactate dehydrogenase (LDH) release in a concentration-dependent manner. Swollen, dead or dying cells were negative for TUNEL staining. The pre-treatment with inhibitors of mitogen-activated/extracellular regulated kinase (MEK1), protein kinase C (PKC) or Ca2+/calmodulin-dependent kinase II (CaMKII) blocked the toxic effects of toxin Bc2 and EqTx-II, suggesting that calcium entry, activation of MEK1, PKC and CaMKII pathways are involved in the cytotoxicity induced by these cytolysins. Conclusion: Cytolysins were shown to be toxic to glioblastoma cells by activating several intracellular signaling pathways and resulting in necrosis-like cell death.