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

Liesbeth Bieghs, Susanne Lub, Karel Fostier, Ken Maes, Els Van Valckenborgh, Eline Menu, He Johnsen, Mette Nyegaard, H Jernberg-Wiklund, Henri Schots, Karin Vanderkerken, Elke De Bruyne

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)11193-11208
Number of pages16
JournalOncotarget
Volume5
Issue number22
DOIs
Publication statusPublished - 30 Apr 2014

Keywords

  • Multiple myeloma
  • preclinical study
  • BH3-mimetic
  • IGF-1 receptor inhibitor
  • mouse model

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