SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK

Yutaka Okawa, Teru Hideshima, Paul Steed, Sonia Vallet, Steven Hall, Ken Huang, John Rice, Amy Barabasz, Brianna Foley, Hiroshi Ikeda, Noopur Raje, Tanyel Kiziltepe, Hiroshi Yasui, Sotaro Enatsu, Kenneth C. Anderson

Research output: Journal article (peer-reviewed)Journal article

189 Citations (Scopus)

Abstract

Heat-shock protein 90 (Hsp90) acts as a molecular chaperone required for maintain- ing the conformational stability of client proteins regulating cell proliferation, sur- vival, and apoptosis. Here we investigate the biologic significance of Hsp90 inhibition in multiple myeloma (MM) and other hemato- logic tumors using an orally available novel small molecule inhibitor SNX-2112, which exhibits unique activities relative to 17- allyamino-17-demethoxy- geldanamycin (17- AAG). SNX-2112 triggers growth inhibition and is more potent than 17-AAG against MM and other malignancies. It induces apopto- sis via caspase-8, -9, -3, and poly (ADP- ribose) polymerase cleavage. SNX-2112 in- hibits cytokine-induced Akt and extracellular signal-related kinase (ERK) activation and also overcomes the growth advantages con- ferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. Importantly, SNX-2112 inhibits tube forma- tion by human umbilical vein endothelial cells via abrogation of eNOS/Akt pathway and markedly inhibits osteoclast formation via down-regulation of ERK/c-fos and PU.1. Finally, SNX-2112, delivered by its prodrug SNX-5422, inhibits MM cell growth and pro- longs survival in a xenograft murine model. Our results indicate that blockade of Hsp90 by SNX-2112 not only inhibits MM cell growth but also acts in the bone marrow microenvi- ronment to block angiogenesis and oste- oclastogenesis. Taken together, our data provide the framework for clinical studies of SNX-2112 to improve patient outcome in MM and other hematologic malignancies.

Original languageEnglish
Pages (from-to)846-855
Number of pages10
JournalBlood
Volume113
Issue number4
DOIs
Publication statusPublished - 22 Jan 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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