Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Oncogene. 2011 Feb 10;30(6):701-13. doi: 10.1038/onc.2010.441. Epub 2010 Oct 11.
In recent years considerable progress has been made in treatment strategies for chronic lymphocytic leukemia (CLL). However, the disease remains incurable because of the development of chemoresistance. Strategies to overcome resistance mechanisms are therefore highly needed. At least two mechanisms contribute to the development of resistance to drugs; acquired mutations resulting in a dysfunctional p53 response and shifts in the balance between apoptosis-regulating proteins. Platinum-based compounds have been successfully applied in relapsed lymphoma and recently also in high-risk CLL. In this study we investigated the efficacy and mechanism of action of cisplatinum (CDDP) in chemorefractory CLL. Independent of p53-functional status, CDDP acted synergistically with fludarabine (F-ara-A). The response involved generation of reactive oxygen species (ROS), which led to specific upregulation of the proapoptotic BH3-only protein Noxa. Induction of Noxa resulted in cell death by apoptosis as inhibition of caspase activation completely abrogated cell death. Furthermore, drug-resistance upon CD40-ligand stimulation, a model for the protective stimuli provided in lymph nodes, could also be overcome by CDDP/F-ara-A. ROS accumulation resulted in Noxa upregulation mainly at the transcriptional level and this was, at least in part, mediated by the mitogen-activated protein kinase p38. Finally, Noxa RNA-interference markedly decreased sensitivity to CDDP/F-ara-A, supporting a key role for Noxa as mediator between ROS signaling and apoptosis induction. Our data indicate that interference in the cellular redox balance can be exploited to overcome chemoresistance in CLL.
近年来，慢性淋巴细胞白血病（CLL）的治疗策略取得了相当大的进展。然而，由于化疗耐药性的发展，该疾病仍然无法治愈。因此，非常需要克服耐药机制的策略。至少有两种机制导致对药物的耐药性发展；导致 p53 反应功能障碍的获得性突变和凋亡调节蛋白之间平衡的转移。铂类化合物已成功应用于复发性淋巴瘤，最近也应用于高危 CLL。在这项研究中，我们研究了顺铂（CDDP）在化疗耐药性 CLL 中的疗效和作用机制。独立于 p53 功能状态，CDDP 与氟达拉滨（F-ara-A）协同作用。反应涉及活性氧物质（ROS）的产生，这导致促凋亡 BH3 仅蛋白 Noxa 的特异性上调。Noxa 的诱导导致细胞凋亡死亡，因为 caspase 激活的抑制完全消除了细胞死亡。此外，通过 CD40 配体刺激（淋巴结中提供的保护刺激的模型）产生的耐药性也可以被 CDDP/F-ara-A 克服。ROS 积累导致 Noxa 主要在转录水平上调，这至少部分是由丝裂原活化蛋白激酶 p38 介导的。最后，Noxa RNA 干扰显著降低了对 CDDP/F-ara-A 的敏感性，支持 Noxa 作为 ROS 信号转导和凋亡诱导之间的中介物的关键作用。我们的数据表明，细胞氧化还原平衡的干扰可以被利用来克服 CLL 中的化疗耐药性。
