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 and Vivaldo Moura-Neto
Affiliation: Instituto de Ciencias Biomedicas, CCS - Bloco F, Universidade Federal do Rio de Janeiro, 21949-590, Rio de Janeiro, Brazil.
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.
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