title: The IGF-1 receptor inhibitor picropodophyllin potentiates the anti-myeloma activity of a BH3-mimetic.
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.
authors.affiliation: 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.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Bieghs
authors.affiliation: Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Susanne
authors.initials: S
authors.lastname: Lub
authors.affiliation: Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Fostier
authors.affiliation: Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ken
authors.initials: K
authors.lastname: Maes
authors.affiliation: Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Van Valckenborgh
authors.affiliation: Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Eline
authors.initials: E
authors.lastname: Menu
authors.affiliation: Department of Haematology, Aalborg Hospital, Aalborg University, Denmark.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Johnsen
authors.affiliation: Department of Chemistry and Biotechnology, Aalborg University, Denmark.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Overgaard
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Axelson
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Nyegaard
authors.affiliation: Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Schots
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Jernberg-Wiklund
authors.affiliation: Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.affiliation: Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Elke
authors.initials: E
authors.lastname: De Bruyne
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D040761:Biomimetic Materials / Q000008:administration & dosage / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011034:Podophyllotoxin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; C415032:picropodophyllin; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin