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
  • 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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