Canonical Wnt pathway inhibitor ICG-001 induces cytotoxicity of multiple myeloma cells in Wnt-independent manner.

Abstract

Canonical Wnt signaling has been implicated in the regulation of multiple myeloma (MM) growth. Here, we investigated whether the targeting of this pathway with a novel pharmacological inhibitor ICG-001 would result in an anti-tumor effect and improvement of chemosensitivity in MM. As expected, ICG-001 specifically down-regulated β-catenin/TCF-mediated transcription in MM cells. Treatment with ICG-001 resulted in growth arrest and apoptosis in MM cell lines and primary MM cells. Moreover, ICG-001 enhanced the cytotoxic effects of doxorubicin and melphalan and abrogated chemoresistance of MM cells to these chemotherapeutics induced by bone marrow stroma. The cytotoxic effect of ICG-001 was caspase-dependent and mediated through transcriptional up-regulation of BH3-only pro-apoptotic members of the Bcl-2 family Noxa and Puma but not through inhibition of canonical Wnt signaling. ICG-001 selectively induced apoptosis in primary MM cells but did not affect non-MM cells of the bone marrow microenvironment. Experiments using a xenograft model of MM showed substantial anti-tumor effects of this compound in vivo. Thus, our study demonstrated that the small molecule inhibitor ICG-001 has strong anti-MM effects and could be developed further for therapeutic intervention in this disease.

• Authors: Eileen R Grigson, Maria Ozerova, Alexandra Pisklakova, Hao Liu, Daniel M Sullivan, Yulia Nefedova
• Journal: PloS one (PLoS One) Vol. 10 Issue 1 Pg. e0117693 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25635944 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• ICG 001
• Pyrimidinones
• Wnt Proteins

Topics

• Animals
• Bone Marrow Cells (drug effects, metabolism)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Mice
• Multiple Myeloma (pathology)
• Pyrimidinones (pharmacology)
• Stromal Cells (drug effects, metabolism)
• Tumor Burden (drug effects)
• Wnt Proteins (metabolism)
• Wnt Signaling Pathway (drug effects)
• Xenograft Model Antitumor Assays