2. Academic Validation
  3. The IGF-1 receptor inhibitor picropodophyllin potentiates the anti-myeloma activity of a BH3-mimetic

The IGF-1 receptor inhibitor picropodophyllin potentiates the anti-myeloma activity of a BH3-mimetic

  • Oncotarget. 2014 Nov 30;5(22):11193-208. doi: 10.18632/oncotarget.1933.
Liesbeth Bieghs 1,  Susanne Lub 2,  Karel Fostier 2,  Ken Maes 2,  Els Van Valckenborgh 2,  Eline Menu 2,  Hans E Johnsen 3,  Michael T Overgaard 4,  Olle Larsson 5,  Magnus Axelson 6,  Mette Nyegaard 7,  Rik Schots 2,  Helena Jernberg-Wiklund 8,  Karin Vanderkerken 2,  Elke De Bruyne 2
Affiliations

Affiliations

  • 1 Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium. Department of Haematology, Aalborg Hospital, Aalborg University, Denmark. Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • 2 Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
  • 3 Department of Haematology, Aalborg Hospital, Aalborg University, Denmark.
  • 4 Department of Chemistry and Biotechnology, Aalborg University, Denmark.
  • 5 Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
  • 6 Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden.
  • 7 Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • 8 Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden.
PMID: 25008202 DOI: 10.18632/oncotarget.1933
Abstract

The ABT-analogous 737, 263 and 199 are BH3 mimetics showing potent anti-myeloma (MM) activity, but only on defined molecular subgroups of MM patients presenting a Bcl-2high/Mcl-1low profile. IGF-1 is a major survival factor in MM regulating the expression of Bcl-2 proteins and might therefore be a resistance factor to these ABT-analogous. We first show that IGF-1 protected human MM cell lines (HMCLs) against ABT-737. Concurrently, the IGF-1 receptor inhibitor picropodophyllin (PPP) synergistically sensitized HMCL, primary human MM and murine 5T33MM cells to ABT-737 and ABT-199 by further decreasing cell viability and enhancing Apoptosis. Knockdown of Bcl-2 by shRNA protected MM cells to ABT-737, while Mcl-1 shRNA sensitized the cells. PPP overcame the Bcl-2 dependency of ABT-737, but failed to completely overcome the protective effect of Mcl-1. In vivo, co-treatment of 5T33MM bearing mice significantly decreased tumor burden and prolonged overall survival both in a prophylactic and therapeutic setting. Interestingly, Proteasome Inhibitor resistant CD138- 5T33MM cells were more sensitive to ABT-737, whereas PPP alone targeted the CD138+ cells more effectively. After co-treatment, both subpopulations were targeted equally. Together, the combination of an IGF-1R Inhibitor and an ABT-analogue displays synergistic anti-myeloma activity providing the rational for further (pre)clinical testing.

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