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

// Liesbeth Bieghs 1,2,3 , Susanne Lub 1 , Karel Fostier 1 , Ken Maes 1 , Els Van Valckenborgh 1 , Eline Menu 1 , Hans E. Johnsen 2 , Michael T. Overgaard 4 , Olle Larsson 5 , Magnus Axelson 6 , Mette Nyegaard 3 , Rik Schots 1 , Helena Jernberg-Wiklund 7 , Karin Vanderkerken 1,* and Elke De Bruyne 1,* 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 Correspondence: 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 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-2 high /Mcl-1 low 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.