Garofalo Stefano, Grimaldi Alfonso, Chece Giuseppina, Porzia Alessandra, Morrone Stefania, Mainiero Fabrizio, D'Alessandro Giuseppina, Esposito Vincenzo, Cortese Barbara, Di Angelantonio Silvia, Trettel Flavia, Limatola Cristina
Department of Physiology and Pharmacology.
Istituto di Ricovero e Cura a Carattere Scientifico, Neuromed, 86077 Pozzilli, Italy.
J Neurosci. 2017 Apr 5;37(14):3926-3939. doi: 10.1523/JNEUROSCI.2296-16.2017. Epub 2017 Mar 14.
Oleandrin is a glycoside that inhibits the ubiquitous enzyme Na/K-ATPase. In addition to its known effects on cardiac muscle, recent and evidence highlighted its potential for anticancer properties. Here, we evaluated for the first time the effect of oleandrin on brain tumors. To this aim, mice were transplanted with human or murine glioma and analyzed for tumor progression upon oleandrin treatment. In both systems, oleandrin impaired glioma development, reduced tumor size, and inhibited cell proliferation. We demonstrated that oleandrin does the following: (1) enhances the brain-derived neurotrophic factor (BDNF) level in the brain; (2) reduces both microglia/macrophage infiltration and CD68 immunoreactivity in the tumor mass; (3) decreases astrogliosis in peritumoral area; and (4) reduces glioma cell infiltration in healthy parenchyma. In BDNF-deficient mice (bdnftm1Jae/J) and in glioma cells silenced for TrkB receptor expression, oleandrin was not effective, indicating a crucial role for BDNF in oleandrin's protective and antitumor functions. In addition, we found that oleandrin increases survival of temozolomide-treated mice. These results encourage the development of oleandrin as possible coadjuvant agent in clinical trials of glioma treatment. In this work, we paved the road for a new therapeutic approach for the treatment of brain tumors, demonstrating the potential of using the cardioactive glycoside oleandrin as a coadjuvant drug to standard chemotherapeutics such as temozolomide. In murine models of glioma, we demonstrated that oleandrin significantly increased mouse survival and reduced tumor growth both directly on tumor cells and indirectly by promoting an antitumor brain microenvironment with a key protective role played by the neurotrophin brain-derived neurotrophic factor.
夹竹桃苷是一种抑制普遍存在的钠钾ATP酶的糖苷。除了其对心肌的已知作用外，最近的证据突出了其抗癌特性的潜力。在此，我们首次评估了夹竹桃苷对脑肿瘤的影响。为此，将人或鼠胶质瘤移植到小鼠体内，并分析夹竹桃苷治疗后的肿瘤进展情况。在这两种模型中，夹竹桃苷均损害胶质瘤的发展，减小肿瘤大小并抑制细胞增殖。我们证明夹竹桃苷具有以下作用：（1）提高脑中脑源性神经营养因子（BDNF）的水平；（2）减少肿瘤组织中小胶质细胞/巨噬细胞浸润和CD68免疫反应性；（3）降低肿瘤周围区域的星形胶质细胞增生；（4）减少胶质瘤细胞向健康实质组织的浸润。在BDNF缺陷小鼠（bdnftm1Jae/J）和TrkB受体表达沉默的胶质瘤细胞中，夹竹桃苷无效，这表明BDNF在夹竹桃苷的保护和抗肿瘤功能中起关键作用。此外，我们发现夹竹桃苷可提高替莫唑胺治疗小鼠的存活率。这些结果鼓励在胶质瘤治疗的临床试验中开发夹竹桃苷作为可能的辅助剂。在这项工作中，我们为脑肿瘤治疗的新治疗方法铺平了道路，证明了使用具有心脏活性的糖苷夹竹桃苷作为替莫唑胺等标准化疗药物的辅助药物的潜力。在胶质瘤的小鼠模型中，我们证明夹竹桃苷直接作用于肿瘤细胞并通过促进具有神经营养因子脑源性神经营养因子发挥关键保护作用的抗肿瘤脑微环境间接显著提高小鼠存活率并减少肿瘤生长。
