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

Oncogene. 2011 Feb 10;30(6):701-13. doi: 10.1038/onc.2010.441. Epub 2010 Oct 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / metabolism
  • CD40 Antigens / metabolism
  • Cisplatin / metabolism
  • Cisplatin / therapeutic use
  • Drug Resistance, Neoplasm*
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Middle Aged
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Tumor Cells, Cultured
  • Up-Regulation
  • Vidarabine / analogs & derivatives
  • Vidarabine / metabolism
  • Vidarabine / therapeutic use
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • CD40 Antigens
  • PMAIP1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • p38 Mitogen-Activated Protein Kinases
  • Vidarabine
  • fludarabine
  • Cisplatin