Recent studies have suggested that the proliferation of
malignant gliomas may result from activation of
protein kinase C (PKC)-mediated pathways.
Enzastaurin (LY317615), an acyclic
bisindolylmaleimide, is an oral inhibitor of PKCbeta as well as other
isoforms. The initial objective of this study was to assess the efficacy of
enzastaurin in a series of malignant human
glioma cell lines with diverse genomic alterations. Although
enzastaurin independently produced a dose-dependent inhibition of cellular proliferation and decreased cell viability in each of the
glioma cell lines examined, and partially down-regulated Akt and
GSK3beta phosphorylation, median effective concentrations were at the upper limits of, or above, the clinically achievable range in all cell lines tested. We therefore examined whether the efficacy of
enzastaurin could be enhanced by combination with the HSP90 antagonist,
17-AAG, which inhibits Akt and other signaling intermediates by a distinct mechanism. In comparison to the effect of
enzastaurin alone, combination of
enzastaurin with
17-AAG led to marked enhancement of antiproliferative and cytotoxic effects. Simultaneous exposure to both agents significantly increased the release of
cytochrome c, as well as
caspase 3 activation, Bax cleavage, and inhibition of Akt phosphorylation. Cells exposed to
enzastaurin and
17-AAG also displayed a significant reduction in
cell cycle regulatory proteins, such as CDK4 and CDK6. Taken together, these findings suggest that the efficacy of
enzastaurin can be potentiated by the addition of
17-AAG, and indicate that combining molecularly targeted
therapies may provide a more effective strategy than single-agent
therapy to treat patients with
malignant gliomas.