The IGF-1 receptor inhibitor picropodophyllin potentiates the anti-myeloma activity of a BH3-mimetic
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Liesbeth Bieghs1,2,3, Susanne Lub1, Karel Fostier1, Ken Maes1, Els Van Valckenborgh1, Eline Menu1, Hans E. Johnsen2, Michael T. Overgaard4, Olle Larsson5, Magnus Axelson6, Mette Nyegaard3, Rik Schots1, Helena Jernberg-Wiklund7, Karin Vanderkerken1,* and Elke De Bruyne1,*
1 Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium
2 Department of Haematology, Aalborg Hospital, Aalborg University, Denmark
3 Department of Biomedicine, Aarhus University, Aarhus, 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 Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden
* These are equal senior authors
Elke De Bruyne, email:
Keywords: Multiple myeloma, IGF-1 receptor inhibitor, BH3-mimetic, preclinical study, mouse model
Received: February 26, 2014 Accepted: April 30, 2014 Published: April 30, 2014
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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