Advanced Center for Research and Development in Experimental Medicine, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania; Department of Medical Oncology, Regional Institute of Oncology, Iasi, Romania.
Department of Neurobiology, Institute of Biological Research "Siniša Stanković", University of Belgrade, Serbia.
Drug Resist Updat. 2019 Sep;46:100643. doi: 10.1016/j.drup.2019.100643. Epub 2019 Aug 23.
Identification of multidrug (MDR) efflux transporters that belong to the ATP-Binding Cassette (ABC) superfamily, represented an important breakthrough for understanding cancer multidrug resistance (MDR) and its possible overcoming. However, recent data indicate that drug resistant cells have a complex intracellular physiology that involves constant changes in energetic and oxidative-reductive metabolic pathways, as well as in the molecular circuitries connecting mitochondria, endoplasmic reticulum (ER) and lysosomes. The aim of this review is to discuss the key molecular mechanisms of cellular reprogramming that induce and maintain MDR, beyond the presence of MDR efflux transporters. We specifically highlight how cancer cells characterized by high metabolic plasticity - i.e. cells able to shift the energy metabolism between glycolysis and oxidative phosphorylation, to survive both the normoxic and hypoxic conditions, to modify the cytosolic and mitochondrial oxidative-reductive metabolism, are more prone to adapt to exogenous stressors such as anti-cancer drugs and acquire a MDR phenotype. Similarly, we discuss how changes in mitochondria dynamics and mitophagy rates, changes in proteome stability ensuring non-oncogenic proteostatic mechanisms, changes in ubiquitin/proteasome- and autophagy/lysosome-related pathways, promote the cellular survival under stress conditions, along with the acquisition or maintenance of MDR. After dissecting the complex intracellular crosstalk that takes place during the development of MDR, we suggest that mapping the specific adaptation pathways underlying cell survival in response to stress and targeting these pathways with potent pharmacologic agents may be a new approach to enhance therapeutic efficacy against MDR tumors.
鉴定属于三磷酸腺苷结合盒（ABC）超家族的多药（MDR）外排转运蛋白，是理解癌症多药耐药（MDR）及其可能克服的重要突破。然而，最近的数据表明，耐药细胞具有复杂的细胞内生理学，涉及能量和氧化还原代谢途径的不断变化，以及连接线粒体、内质网（ER）和溶酶体的分子电路的变化。本综述的目的是讨论诱导和维持 MDR 的细胞重编程的关键分子机制，而不仅仅是存在 MDR 外排转运蛋白。我们特别强调了具有高代谢可塑性的癌细胞（即能够在糖酵解和氧化磷酸化之间转换能量代谢以在常氧和缺氧条件下存活、改变细胞质和线粒体氧化还原代谢的细胞）如何更容易适应外源性应激源，如抗癌药物，并获得 MDR 表型。同样，我们讨论了线粒体动力学和自噬率的变化、确保非致癌蛋白稳定的蛋白质组稳定性变化、泛素/蛋白酶体和自噬/溶酶体相关途径的变化如何促进细胞在应激条件下的存活，以及 MDR 的获得或维持。在剖析 MDR 发展过程中发生的复杂细胞内串扰之后，我们建议绘制细胞在应激反应中存活的特定适应途径，并使用有效的药物靶向这些途径，可能是增强针对 MDR 肿瘤的治疗效果的新方法。
