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ROS-mediated upregulation of Noxa overcomes chemoresistance in chronic lymphocytic leukemia

Oncogene volume 30, pages 701–713 (2011)Cite this article

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Abstract

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.

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Acknowledgements

We thank M Baou and GM Cohen of the MRC Toxicology Unit, University of Leicester, United Kingdom for sharing their experience with nucleofection-procedures. APK is personally supported by a ‘Veni’ grant from the Netherlands Organization for Health Research and Development.

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Authors and Affiliations

  1. Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    S H Tonino, M H van Oers & A P Kater

  2. Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    J van Laar & E Eldering

  3. Department of Medicine and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

    J Y Wang

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  1. S H Tonino
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  2. J van Laar
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  3. M H van Oers
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Correspondence to A P Kater.

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Tonino, S., van Laar, J., van Oers, M. et al. ROS-mediated upregulation of Noxa overcomes chemoresistance in chronic lymphocytic leukemia. Oncogene 30, 701–713 (2011). https://doi.org/10.1038/onc.2010.441

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