Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving, showing that this area of biomedical research attracts great interest in the scientific community. The current review explores promising recent approaches that have been developed with the aim of circumventing or overcoming MDR. Encouraging results have been obtained in the investigation of the MDR-modulating properties of various classes of natural compounds and their analogues. Inhibition of P-gp or downregulation of its expression have proven to be the main mechanisms by which MDR can be surmounted. The use of hybrid molecules that are able to simultaneously interact with two or more cancer cell targets is currently being explored as a means to circumvent drug resistance. This strategy is based on the design of hybrid compounds that are obtained either by merging the structural features of separate drugs, or by conjugating two drugs or pharmacophores via cleavable/non-cleavable linkers. The approach is highly promising due to the pharmacokinetic and pharmacodynamic advantages that can be achieved over the independent administration of the two individual components. However, it should be stressed that the task of obtaining successful multivalent drugs is a very challenging one. The conjugation of anticancer agents with nitric oxide (NO) donors has recently been developed, creating a particular class of hybrid that can combat tumor drug resistance. Appropriate NO donors have been shown to reverse drug resistance via nitration of ABC transporters and by interfering with a number of metabolic enzymes and signaling pathways. In fact, hybrid compounds that are produced by covalently attaching NO-donors and antitumor drugs have been shown to elicit a synergistic cytotoxic effect in a variety of drug resistant cancer cell lines. Another strategy to circumvent MDR is based on nanocarrier-mediated transport and the controlled release of chemotherapeutic drugs and P-gp inhibitors. Their pharmacokinetics are governed by the nanoparticle or polymer carrier and make use of the enhanced permeation and retention (EPR) effect, which can increase selective delivery to cancer cells. These systems are usually internalized by cancer cells via endocytosis and accumulate in endosomes and lysosomes, thus preventing rapid efflux. Other modalities to combat MDR are described in this review, including the pharmaco-modulation of acridine, which is a well-known scaffold in the development of bioactive compounds, the use of natural compounds as means to reverse MDR, and the conjugation of anticancer drugs with carriers that target specific tumor-cell components. Finally, the outstanding potential of in silico structure-based methods as a means to evaluate the ability of antitumor drugs to interact with drug transporters is also highlighted in this review. Structure-based design methods, which utilize 3D structural data of proteins and their complexes with ligands, are the most effective of the in silico methods available, as they provide a prediction regarding the interaction between transport proteins and their substrates and inhibitors. The recently resolved X-ray structure of human P-gp can help predict the interaction sites of designed compounds, providing insight into their binding mode and directing possible rational modifications to prevent them from becoming P-gp drug substrates. In summary, although major efforts were invested in the search for new tools to combat drug resistant tumors, they all require further implementation and methodological development. Further investigation and progress in the abovementioned strategies will provide significant advances in the rational combat against cancer MDR.

多药耐药性（MDR）是癌症化疗失败的主要原因。能够规避耐多药耐药性的抗肿瘤药物的设计正在迅速发展，这表明生物医学研究领域引起了科学界的极大兴趣。本篇综述探讨了为避免或克服MDR而开发的有希望的最新方法。在研究各类天然化合物及其类似物的MDR调节特性时，获得了令人鼓舞的结果。事实证明，抑制P-gp或使其表达下调是克服MDR的主要机制。目前正在探索使用能够同时与两个或多个癌细胞靶标相互作用的杂合分子作为规避耐药性的手段。该策略基于杂化化合物的设计，该杂化化合物通过合并不同药物的结构特征或通过可裂解/不可裂解的接头缀合两种药物或药效团而获得。由于该药代动力学和药效学优势优于两种单独成分的独立给药，因此该方法非常有前途。但是，应该强调的是，获得成功的多价药物是一项非常具有挑战性的任务。抗癌剂与一氧化氮（NO）供体的缀合最近得到了发展，创造了可以对抗肿瘤药物抗性的一类特殊的杂种。适当的NO供体已被证明可通过ABC转运蛋白的硝化作用以及干扰许多代谢酶和信号通路来逆转耐药性。实际上，已经显示出通过共价连接NO供体和抗肿瘤药物而产生的杂合化合物在多种耐药性癌细胞系中引起协同的细胞毒性作用。规避MDR的另一种策略是基于纳米载体介导的转运以及化学治疗药物和P-gp抑制剂的控制释放。它们的药代动力学受纳米颗粒或聚合物载体的控制，并利用增强的渗透和保留（EPR）效应，可以增加对癌细胞的选择性递送。这些系统通常会通过内吞作用被癌细胞内化并积累在内体和溶酶体中，从而防止快速流出。本综述中还描述了其他对抗MDR的方式，包括the啶的药物调节，which啶是生物活性化合物开发中众所周知的支架，使用天然化合物作为逆转MDR的手段，以及抗癌药物的结合带有靶向特定肿瘤细胞成分的载体。最后，巨大的潜力本文还重点介绍了基于计算机模拟结构的方法，以评估抗肿瘤药物与药物转运蛋白相互作用的能力。利用蛋白质及其配体配合物的3D结构数据的基于结构的设计方法是计算机上最有效的方法可用的方法，因为它们提供了有关转运蛋白与其底物和抑制剂之间相互作用的预测。最近解析的人类P-gp的X射线结构可以帮助预测设计化合物的相互作用位点，从而洞悉它们的结合模式并指导可能的合理修饰以防止它们成为P-gp药物底物。总而言之，尽管人们投入了巨大的精力来寻找新的工具来对抗耐药性肿瘤，但它们都需要进一步的实施和方法学的发展。上述策略的进一步研究和进展将在合理对抗癌症MDR方面提供重要进展。