Annals of Hematology

, Volume 91, Issue 6, pp 847–856

The proteasome inhibitor bortezomib targets cell cycle and apoptosis and acts synergistically in a sequence-dependent way with chemotherapeutic agents in mantle cell lymphoma

  • Grit Hutter
  • Malte Rieken
  • Alessandro Pastore
  • Oliver Weigert
  • Yvonne Zimmermann
  • Marc Weinkauf
  • Wolfgang Hiddemann
  • Martin Dreyling
Original Article

Abstract

Single-agent bortezomib, a potent, selective, and reversible inhibitor of the 26S proteasome, has demonstrated clinical efficacy in relapsed and refractory mantle cell lymphoma (MCL). Objective response is achieved in up to 45% of the MCL patients; however, complete remission rates are low and duration of response proved to be relatively short. These limitations may be overcome by combining proteasome inhibition with conventional chemotherapy. Rational combination treatment and schedules require profound knowledge of underlying molecular mechanisms. Here we show that single-agent bortezomib treatment of MCL cell lines leads to G2/M arrest and induction of apoptosis accompanied by downregulation of EIF4E and CCND1 mRNA but upregulation of p15(INK4B) and p21 mRNA. We further present synergistic efficacy of bortezomib combined with cytarabine in MCL cell lines. Interestingly this sequence-dependent synergistic effect was seen almost exclusively in combination with AraC, indicating that pretreatment with cytarabine, followed by proteasome inhibition, may be the preferred approach.

Keywords

MCL Bortezomib AraC Apoptosis Cell cycle arrest 

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Grit Hutter
    • 2
  • Malte Rieken
    • 3
  • Alessandro Pastore
    • 1
    • 2
  • Oliver Weigert
    • 1
    • 2
  • Yvonne Zimmermann
    • 2
  • Marc Weinkauf
    • 2
  • Wolfgang Hiddemann
    • 1
  • Martin Dreyling
    • 1
    • 2
  1. 1.Department of Medicine IIIUniversity Hospital GrosshadernMunichGermany
  2. 2.Helmholtz Centre MunichMuenchenGermany
  3. 3.Urologische KlinikUniversitätsspital BaselBaselSwitzerland

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