Equinatoxin II Potentiates Temozolomide- and Etoposide-Induced Glioblastoma Cell Death

Suzana   Assad   Kahn; Deborah      Biasoli; Celina      Garcia; Luiz   Henrique M.   Geraldo; Bruno      Pontes; Morgana      Sobrinho; Ana   Carina Bon   Frauches; Luciana      Romao; Rossana   C.   Soletti; Fernando   dos Santos   Assuncao; Fernanda      Tovar-Moll; Jorge   Marcondes   de Souza; Flavia   R.S.   Lima; Gregor      Anderluh; Vivaldo      Moura-Neto

Abstract

Glioblastoma (GBM) is considered incurable due to its resistance to current cancer treatments. So far, all clinically available alternatives for treating GBM are limited, evoking the development of novel treatment strategies that can more effectively manage these tumors. Extensive effort is being dedicated to characterize the molecular basis of GBM resistance to chemotherapy and to explore novel therapeutic procedures that may improve overall survival. Cytolysins are toxins that form pores in target cell membranes, modifying ion homeostasis and leading to cell death. These pore-forming toxins might be used, therefore, to enhance the efficiency of conventional chemotherapeutic drugs, facilitating their entrance into the cell. In this study, we show that a non-cytotoxic concentration of equinatoxin II (EqTx-II), a pore-forming toxin from the sea anemone Actinia equina, potentiates the cytotoxicity induced by temozolomide (TMZ), a first-line GBM treatment, and by etoposide (VP-16), a second- or third-line GBM treatment. We also suggest that this effect is selective to GBM cells and occurs via PI3K/Akt pathway inhibition. Finally, Magnetic resonance imaging (MRI) revealed that a non-cytotoxic concentration of EqTx-II potentiates the VP-16-induced inhibition of GBM growth in vivo. These combined therapies constitute a new and potentially valuable tool for GBM treatment, leading to the requirement of lower concentrations of chemotherapeutic drugs and possibly reducing, therefore, the adverse effects of chemotherapy.

Keywords: glioblastoma, equinatoxin II, temozolomide, etoposide, chemotherapeutic drugs, novel treatment strategies, Cytolysins, novel therapeutic procedures, chemotherapy, cell death, Actinia equina.