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Dll1/Notch activation contributes to bortezomib resistance by upregulating CYP1A1 in multiple myeloma

Dehui Xu1, Jinsong Hu, Elke De Bruyne

  • 1Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.

Biochemical and Biophysical Research Communications
|November 1, 2012
PubMed

Insights

Blocking Notch signaling with DAPT enhances bortezomib efficacy in multiple myeloma (MM) by reversing drug resistance. This approach, targeting the Dll1/Notch2 pathway and CYP1A1, offers a promising strategy for MM treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Drug resistance remains a significant challenge in multiple myeloma (MM) treatment.
  • Notch signaling, involving Notch receptors on MM cells and Dll1 ligand on bone marrow stromal cells, is implicated in MM pathogenesis and drug resistance.

Purpose of the Study:

  • To investigate the role of the Dll1/Notch pathway in bortezomib resistance in multiple myeloma.
  • To evaluate the therapeutic potential of inhibiting Notch signaling to overcome bortezomib resistance.

Main Methods:

  • Activation of Notch signaling via Dll1 in murine and human MM cells.
  • Inhibition of Notch pathway using DAPT (gamma secretase inhibitor).
  • Assessment of bortezomib sensitivity and CYP1A1 expression.
  • In vivo studies using the 5T33MM mouse model.

Main Results:

  • Dll1 activates Notch signaling, primarily through Notch2, contributing to bortezomib resistance in MM cells.
  • DAPT treatment reversed Dll1-induced bortezomib resistance and enhanced sensitivity.
  • Upregulation of CYP1A1, a drug-metabolizing enzyme, was identified as a mechanism for Dll1/Notch-mediated bortezomib resistance.
  • Inhibition of CYP1A1 (using α-Naphthoflavone or CYP1A1-siRNA) increased bortezomib sensitivity.
  • Combination therapy with DAPT and bortezomib prolonged overall survival in a mouse model.

Conclusions:

  • The Dll1/Notch2 pathway contributes to bortezomib resistance in multiple myeloma, partly via CYP1A1 upregulation.
  • Inhibiting Notch signaling represents a viable strategy to enhance bortezomib efficacy and overcome resistance in MM therapy.

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