Mitochondrial Dysfunction in Gliomas: Pharmacotherapeutic Potential of Natural Compounds.
Mitochondrial Dysfunction in Gliomas: Pharmacotherapeutic Potential of Natural Compounds.
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DOI：
10.2174/1570159x14666160121115641
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发表时间：
2016
影响因子：
5.3
通讯作者：
Yerra VG
中科院分区：
文献类型：
--
作者：
Guntuku L;Naidu VG;Yerra VG
胶质瘤是最常见的原发性脑肿瘤，无论是良性还是恶性，都起源于神经胶质组织。多形性胶质母细胞瘤（GBM）是所有胶质瘤中最常见且侵袭性最强的类型，由于其高度侵袭性，预后不佳。GBM还具有高复发率和抗凋亡的特征，这使得治疗靶向极具挑战性。线粒体是关键的细胞器，在多种细胞功能中起着核心作用，例如细胞能量代谢、离子稳态调节、氧化还原信号传导和细胞死亡。线粒体功能障碍的最终表现包括在包括胶质瘤在内的各种恶性肿瘤中经常观察到的糖酵解优先于氧化磷酸化、活性氧生成增加以及线粒体介导的凋亡机制异常。特别是，胶质瘤存在线粒体结构异常、线粒体DNA基因组突变、能量代谢改变（瓦尔堡效应）以及异柠檬酸脱氢酶（IDH）酶突变。许多天然化合物通过靶向线粒体异常信号级联在胶质瘤治疗中显示出疗效。一些天然化合物直接靶向线粒体的组成部分，而另一些则通过调节线粒体功能障碍导致的代谢异常间接起作用。本综述从分子层面深入探讨了胶质瘤中的线粒体病理学以及一些针对线粒体功能障碍的有前景的天然化合物的治疗机制。本综述还阐明了这些天然化合物进入临床市场所面临的挑战以及克服相关障碍的可能方法。
Gliomas are the most common primary brain tumors either benign or malignant originating from the glial tissue. Glioblastoma multiforme (GBM) is the most prevalent and aggressive form among all gliomas, associated with decimal prognosis due to it's high invasive nature. GBM is also characterized by high recurrence rate and apoptosis resistance features which make the therapeutic targeting very challenging. Mitochondria are key cellular organelles that are acting as focal points in diverse array of cellular functions such as cellular energy metabolism, regulation of ion homeostasis, redox signaling and cell death. Eventual findings of mitochondrial dysfunction include preference of glycolysis over oxidative phosphorylation, enhanced reactive oxygen species generation and abnormal mitochondria mediated apoptotic machinery are frequently observed in various malignancies including gliomas. In particular, gliomas harbor mitochondrial structure abnormalities, genomic mutations in mtDNA, altered energy metabolism (Warburg effect) along with mutations in isocitrate dehydrogenase (IDH) enzyme. Numerous natural compounds have shown efficacy in the treatment of gliomas by targeting mitochondrial aberrant signaling cascades. Some of the natural compounds directly target the components of mitochondria whereas others act indirectly through modulating metabolic abnormalities that are consequence of the mitochondrial dysfunction. The present review offers a molecular insight into mitochondrial pathology in gliomas and therapeutic mechanisms of some of the promising natural compounds that target mitochondrial dysfunction. This review also sheds light on the challenges and possible ways to overcome the hurdles associated with these natural compounds to enter into the clinical market.