Department of Organic and Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago de Chile.
Curr Top Med Chem. 2013;13(17):2171-83. doi: 10.2174/15680266113139990150.
A great number of alkaloids exhibit high potential in cancer research. Some of them are anticancer drugs with well-defined clinical uses, exerting their action on microtubules dynamics or DNA replication and topology. On the other hand, mitochondria have been recognized as an essential organelle in the establishment of tumor characteristics, especially the resistance to cell death, high proliferative capacity and adaptation to unfavorable cellular environment. Interestingly, many alkaloids exert their anticancer activities affecting selectively some functions of the tumor mitochondria by 1) modulating OXPHOS and ADP/ATP transport, 2) increasing ROS levels and mitochondrial potential dissipation by crosstalk between endoplasmic reticulum (ER) and mitochondria, 3) inducing mitochondria-dependent apoptosis and autophagy, 4) inhibiting mitochondrial metabolic pathways and 5) by alteration of the morphology and biogenesis of this organelle. These antecedents show the relevance of developing research about the effects of alkaloids on functions controlled by tumor mitochondria, offering an attractive target for the design of new alkaloid derivatives, considering organelle- specific delivery strategies. This review describes mitochondria as a central component in the anticancer action of a set of alkaloids, in a way to illustrate the importance of this organelle in medicinal chemistry.
大量生物碱在癌症研究中具有很高的潜力。其中一些是具有明确临床用途的抗癌药物，它们通过作用于微管动力学或 DNA 复制和拓扑结构来发挥作用。另一方面，线粒体已被认为是肿瘤特征建立的一个重要细胞器，特别是对细胞死亡、高增殖能力和适应不利细胞环境的抵抗。有趣的是，许多生物碱通过以下方式选择性地影响肿瘤线粒体的某些功能来发挥其抗癌活性：1）调节氧化磷酸化和 ADP/ATP 转运；2）通过内质网（ER）和线粒体之间的串扰增加 ROS 水平和线粒体电位耗散；3）诱导线粒体依赖性细胞凋亡和自噬；4）抑制线粒体代谢途径；5）改变细胞器的形态和发生。这些先例表明，开发关于生物碱对肿瘤线粒体控制的功能的研究具有重要意义，为设计新的生物碱衍生物提供了有吸引力的目标，同时考虑到细胞器特异性的递药策略。本综述将线粒体描述为一组生物碱抗癌作用的核心组成部分，以说明该细胞器在药物化学中的重要性。
