Centre de Recherche en Infectiologie du CHUL, Université Laval, Québec, Quebec, Canada.
Cell Death Dis. 2011 Sep 1;2(9):e201. doi: 10.1038/cddis.2011.83.
The control of the protozoan parasite Leishmania relies on few drugs with unknown cellular targets and unclear mode of action. Several antileishmanials, however, were shown to induce apoptosis in Leishmania and this death mechanism was further studied in drug-sensitive and drug-resistant Leishmania infantum. In sensitive parasites, antimonials (SbIII), miltefosine (MF) and amphotericin B (AMB), but not paromomycin (PARO), triggered apoptotic cell death associated with reactive oxygen species (ROS). In contrast, Leishmania mutants resistant to SbIII, MF or AMB not only failed to undergo apoptosis following exposure to their respective drugs, but also were more tolerant towards apoptosis induced by other antileishmanials, provided that these killed Leishmania via ROS production. Such tolerance favored the rapid acquisition of multidrug resistance. PARO killed Leishmania in a non-apoptotic manner and failed to produce ROS. PARO resistance neither protected against drug-induced apoptosis nor provided an increased rate of acquisition of resistance to other antileishmanials. However, the PARO-resistant mutant, but not SbIII-, MF- or AMB-resistant mutants, became rapidly cross-resistant to methotrexate, a model drug also not producing ROS. Our results therefore link the mode of killing of drugs to tolerance to cell death and to a facilitated emergence of multidrug resistance. These findings may have fundamental implications in the field of chemotherapeutic interventions.
原生动物寄生虫利什曼原虫的控制依赖于少数几种药物，这些药物的细胞靶点未知，作用机制不清楚。然而，几种抗利什曼原虫药物被证明能诱导利什曼原虫细胞凋亡，并且这种死亡机制在敏感和耐药的婴儿利什曼原虫中得到了进一步研究。在敏感寄生虫中，锑剂（SbIII）、米替福新（MF）和两性霉素 B（AMB），但不是巴龙霉素（PARO），会引发与活性氧（ROS）相关的凋亡性细胞死亡。相比之下，对 SbIII、MF 或 AMB 耐药的利什曼原虫突变体不仅在接触各自药物后不能发生细胞凋亡，而且对其他抗利什曼原虫药物诱导的细胞凋亡也有更高的耐受性，只要这些药物通过产生 ROS 来杀死利什曼原虫。这种耐受性有利于快速获得多药耐药性。PARO 以非凋亡的方式杀死利什曼原虫，并且不能产生 ROS。PARO 耐药性既不能保护细胞免受药物诱导的凋亡，也不能增加对其他抗利什曼原虫药物的耐药性获得率。然而，PARO 耐药突变体，而不是 SbIII、MF 或 AMB 耐药突变体，对甲氨蝶呤迅速产生交叉耐药，甲氨蝶呤是一种也不产生 ROS 的模型药物。因此，我们的研究结果将药物的杀伤模式与对细胞死亡的耐受性以及多药耐药性的快速出现联系起来。这些发现可能对抗生素干预领域具有重要意义。
