title: 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: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America; The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors: Eileen R
authors: ER
authors: Grigson
authors: The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors: Maria
authors: M
authors: Ozerova
authors: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors: Alexandra
authors: A
authors: Pisklakova
authors: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors: Hao
authors: H
authors: Liu
authors: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors: Daniel M
authors: DM
authors: Sullivan
authors: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America; The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors: Yulia
authors: Y
authors: Nefedova
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000473:pathology*; D011744:Pyrimidinones / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; D011744:Pyrimidinones; D051153:Wnt Proteins
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