Drug resistance remains a leading cause of chemotherapeutic treatment failure and cancer-related mortality. While some mechanisms of anticancer drug resistance have been well characterized, multiple mechanisms remain elusive. In this respect, passive ion trapping-based lysosomal sequestration of multiple hydrophobic weak-base chemotherapeutic agents was found to reduce the accessibility of these drugs to their target sites, resulting in a markedly reduced cytotoxic effect and drug resistance. Recently we have demonstrated that lysosomal sequestration of hydrophobic weak base drugs triggers TFEB-mediated lysosomal biogenesis resulting in an enlarged lysosomal compartment, capable of enhanced drug sequestration. This study further showed that cancer cells with an increased number of drug-accumulating lysosomes are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. In addition to passive drug sequestration of hydrophobic weak base chemotherapeutics, other mechanisms of lysosome-mediated drug resistance have also been reported; these include active lysosomal drug sequestration mediated by ATP-driven transporters from the ABC superfamily, and a role for lysosomal copper transporters in cancer resistance to platinum-based chemotherapeutics. Furthermore, lysosomal exocytosis was suggested as a mechanism to facilitate the clearance of chemotherapeutics which highly accumulated in lysosomes, thus providing an additional line of resistance, supplementing the organelle entrapment of chemotherapeutics away from their target sites. Along with these mechanisms of lysosome-mediated drug resistance, several approaches were recently developed for the overcoming of drug resistance or exploiting lysosomal drug sequestration, including lysosomal photodestruction and drug-induced lysosomal membrane permeabilization. In this review we explore the current literature addressing the role of lysosomes in mediating cancer drug resistance as well as novel modalities to overcome this chemoresistance.

耐药性仍然是化学疗法治疗失败和癌症相关死亡率的主要原因。虽然已经很好地表征了一些抗癌药物耐药性的机制，但是仍然不清楚多种机制。在这方面，发现多种疏水性弱碱化学治疗剂的基于被动离子俘获的溶酶体螯合减少了这些药物到达其靶位的可及性，从而导致细胞毒性作用和耐药性显着降低。最近，我们已经证明，疏水性弱碱药物的溶酶体隔离可触发TFEB介导的溶酶体生物发生，从而导致溶酶体区室扩大，从而能够增强药物隔离。这项研究进一步表明，具有增加的药物蓄积溶酶体数量的癌细胞对溶酶体分离药物的耐药性更高，这表明了药物诱导的溶酶体介导的化学抗性模型。除了疏水性弱碱化学疗法的被动药物螯合外，还报道了溶酶体介导的耐药性的其他机制。其中包括由ABC超家族的ATP驱动的转运蛋白介导的活性溶酶体药物螯合，以及溶酶体铜转运蛋白在癌症对铂类化学疗法的耐药性中的作用。此外，有人提出溶酶体胞吐作用是促进清除溶酶体中高度积累的化学治疗药物的机制，从而提供了额外的耐药性，补充远离目标部位的化学药剂的细胞器包裹。随着溶酶体介导的耐药性的这些机制，最近开发了几种方法来克服耐药性或利用溶酶体药物隔离，包括溶酶体光解和药物诱导的溶酶体膜通透性。在这篇综述中，我们探索了有关溶酶体在介导抗癌性中的作用以及克服这种化学耐药性的新方法的最新文献。包括溶酶体的光破坏和药物诱导的溶酶体膜通透性。在这篇综述中，我们探索了有关溶酶体在介导抗癌性中的作用以及克服这种化学耐药性的新方法的最新文献。包括溶酶体的光破坏和药物诱导的溶酶体膜通透性。在这篇综述中，我们探索了有关溶酶体在介导抗癌性中的作用以及克服这种化学耐药性的新方法的最新文献。