Instituto de Ciências Biomédicas, CCS - Bloco F, Universidade Federal do Rio de Janeiro, 21949-590, Rio de Janeiro, Brazil.
Curr Top Med Chem. 2012;12(19):2082-93. doi: 10.2174/156802612804910250.
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.
胶质母细胞瘤（GBM）由于对当前癌症治疗的耐药性而被认为是不可治愈的。迄今为止，所有临床可用的治疗 GBM 的替代方法都受到限制，这引发了开发新的治疗策略的需求，以更有效地治疗这些肿瘤。目前正在进行大量努力来阐明 GBM 对化疗耐药的分子基础，并探索可能改善总体生存率的新治疗方法。细胞溶解素是在靶细胞膜上形成孔的毒素，可改变离子平衡并导致细胞死亡。因此，这些成孔毒素可用于增强常规化疗药物的效率，使其更容易进入细胞。在这项研究中，我们表明，海葵 Actinia equina 中的一种成孔毒素 equinatoxin II（EqTx-II）的非细胞毒性浓度可增强替莫唑胺（TMZ）的细胞毒性，TMZ 是 GBM 的一线治疗药物，以及依托泊苷（VP-16），GBM 的二线或三线治疗药物。我们还表明，这种作用对 GBM 细胞具有选择性，并且是通过 PI3K/Akt 途径抑制发生的。最后，磁共振成像（MRI）显示，非细胞毒性浓度的 EqTx-II 可增强 VP-16 诱导的体内 GBM 生长抑制作用。这些联合疗法为 GBM 治疗提供了一种新的、有潜在价值的工具，导致需要较低浓度的化疗药物，从而可能降低化疗的不良反应。
