Retaspimycin hydrochloride (IPI-504), an Hsp90 (
heat shock protein 90) inhibitor, has shown activity in multiple preclinical
cancer models, such as lung, breast and
ovarian cancers. However, its
biological effects in
gliomas and normal brain derived cellular populations remain unknown. In this study, we profiled the expression pattern of Hsp90α/β
mRNA in stable
glioma cell lines, multiple
glioma-derived primary cultures and human neural stem/progenitor cells. The effects of
IPI-504 on cell proliferation, apoptosis, motility and expression of Hsp90 client
proteins were evaluated in
glioma cell lines. In vivo activity of
IPI-504 was investigated in subcutaneous
glioma xenografts. Our results showed Hsp90α and Hsp90β expression levels to be patient-specific, higher in high-grade
glioma-derived primary cells than in low-grade
glioma-derived primary cells, and strongly correlated with CD133 expression and differentiation status of cells. Hsp90 inhibition by
IPI-504 induced apoptosis, blocked migration and invasion, and significantly decreased
epidermal growth factor receptor levels,
mitogen-activated protein kinase and/or Akt activities, and secretion of
vascular endothelial growth factor in
glioma cell lines. In vivo study showed that
IPI-504 could mildly attenuate
tumor growth in immunocompromised mice. These findings suggest that targeting Hsp90 by
IPI-504 has the potential to become an active therapeutic strategy in
gliomas in a selective group of patients, but further research into combination
therapies is still needed.