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.

属于ATP结合盒（ABC）超家族的多药（MDR）外排转运蛋白的鉴定是理解癌症多药耐药性（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，涉及高能和氧化还原代谢途径以及连接线粒体，内质网（ER）和溶酶体的分子回路中的不断变化。这项审查的目的是讨论细胞重编程的关键分子机制，除了存在MDR外排转运蛋白外，还可以诱导和维持MDR。我们特别强调癌细胞具有高代谢可塑性的特征–即 能够在糖酵解和氧化磷酸化之间转移能量代谢，在常氧和低氧条件下存活，改变胞质和线粒体氧化还原代谢的细胞更倾向于适应诸如抗癌药等外源性应激源并获得MDR表型。同样，我们讨论线粒体动力学和线粒体速率的变化，蛋白质组稳定性的变化（确保非致癌性蛋白静息机制），泛素/蛋白酶体和自噬/溶酶体相关途径的变化如何在应激条件下促进细胞存活以及获得性或维护MDR。更容易适应外源应激源，例如抗癌药并获得MDR表型。同样，我们讨论了线粒体动力学和线粒体速率的变化，蛋白质组稳定性的变化（确保非致癌性蛋白静息机制），泛素/蛋白酶体和自噬/溶酶体相关途径的变化如何在应激条件下促进细胞存活以及获得性或维护MDR。更容易适应外源应激源，例如抗癌药并获得MDR表型。同样，我们讨论了线粒体动力学和线粒体速率的变化，蛋白质组稳定性的变化（确保非致癌性蛋白静息机制），泛素/蛋白酶体和自噬/溶酶体相关途径的变化如何在应激条件下促进细胞存活以及获得性或维护MDR。

在解剖了MDR发生过程中发生的复杂细胞内串扰后，我们建议定位潜在的细胞存活响应压力的特定适应途径并用有效的药理剂靶向这些途径可能是增强针对MDR肿瘤的治疗功效的新方法。