The antidepressants maprotiline and fluoxetine induce Type II autophagic cell death in drug-resistant Burkitt's lymphoma
The antidepressants maprotiline and fluoxetine induce Type II autophagic cell death in drug-resistant Burkitt's lymphoma
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DOI：
10.1002/ijc.25477
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发表时间：
2011-04-01
影响因子：
6.4
通讯作者：
Williams, David Clive
中科院分区：
文献类型：
--
作者：
Cloonan, Suzanne M.;Williams, David Clive
对化学疗法的抗性是癌症治疗成功的主要障碍，并且最常见地归因于癌细胞不能通过凋亡（原型程序性细胞死亡（PCD）应答）而死亡。因此，开发能够克服这种对细胞凋亡的抗性并诱导其他形式的细胞死亡的抗癌药物对于有效的癌症治疗至关重要。我们报告说，抗抑郁药马普替林和氟西汀诱导自噬PCD的化疗耐药伯基特淋巴瘤（BL）细胞系DG-75，这不涉及半胱天冬酶，DNA片段化或PARP裂解，但与细胞质空泡的发展，所有一致的PCD的自噬模式。自噬性PCD通过透射电子显微镜、Beclin-I的上调和PCD的程度被自噬抑制剂3-MA降低来证实。相比之下，这些化合物在活检样化学敏感性BL MUTU-I细胞系中诱导凋亡PCD。我们提供的证据表明，化疗耐药DG-75细胞不表达促凋亡Bcl-2蛋白Bax和巴克，显示降低水平的细胞内钙储存和显示缩短的杆状线粒体，所有这些都是已知的与癌细胞中有缺陷的“凋亡”反应。两种细胞系中的PCD对马普替林和氟西汀具有不同的Ca 2+反应，这也可能解释了它们的差异PCD反应。因此，我们的研究支持马普替林和氟西汀作为治疗耐药BL的新型proautophagic剂的新机制作用，因此这些化合物的替代治疗应用。
Resistance to chemotherapy is a major obstacle for the success of cancer therapy and is most commonly attributed to the inability of cancer cells to die by apoptosis, the archetypal programed cell death (PCD) response. The development of anticancer drugs that can overcome this resistance to apoptosis and induce other forms of cell death is therefore paramount for efficient cancer therapy. We report that the antidepressants maprotiline and fluoxetine induce autophagic PCD in the chemoresistant Burkitt's lymphoma (BL) cell line DG-75, which does not involve caspases, DNA fragmentation or PARP cleavage, but is associated with the development of cytoplasmic vacuoles, all consistent with an autophagic mode of PCD. Autophagic PCD was confirmed by transmission electron microscopy, upregulation of Beclin-I and the extent of PCD being reduced by the autophagic inhibitor 3-MA. In contrast, these compounds induced apoptotic PCD in the biopsy-like chemosensitive BL MUTU-I cell line. We provide evidence that the chemoresistant DG-75 cells do not express the proapoptotic Bcl-2 proteins Bax and Bak, show diminished levels of stored intracellular calcium and display shortened rod-like mitochondria, all of which are known to be associated with a defective "apoptotic" response in cancer cells. PCD in the two cell lines has different Ca2+ responses to maprotiline and fluoxetine, which may also account for their differential PCD responses. Our study, therefore, supports a new mechanistic role for maprotiline and fluoxetine as novel proautophagic agents in the treatment of resistant BL, and thus an alternative therapeutic application for these compounds.