In the
tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL)-resistant
glioma cells, treatment with TRAIL in combination with subtoxic doses of
rottlerin induced rapid apoptosis. While the proteolytic processing of
procaspase-3 by TRAIL was partially blocked in these cells, treatment with
rottlerin efficiently recovered TRAIL-induced activation of
caspases. Treatment with
rottlerin significantly decreased Cdc2 activity through the downregulation of
cyclin A,
cyclin B, and Cdc2
proteins, whereas the sensitizing effect of
rottlerin on TRAIL-induced apoptosis was independent of PKCdelta activity. Furthermore, treatment with
rottlerin downregulated the
protein levels of
survivin and X-chromosome-linked IAP (XIAP), two major
caspase inhibitors. Forced expression of Cdc2 together with
cyclin B attenuated
rottlerin-potentiated TRAIL-induced apoptosis by over-riding the
rottlerin-mediated downregulation of
survivin and
XIAP protein levels. Taken together, inhibition of Cdc2 activity and the subsequent downregulation of
survivin and XIAP by subtoxic doses of
rottlerin contribute to amplification of
caspase cascades, thereby overcoming resistance of
glioma cells to TRAIL-mediated apoptosis. Since
rottlerin can sensitize Bcl-2- or Bcl-xL-overexpressing
glioma cells but not human astrocytes to TRAIL-induced apoptosis, this combined treatment may offer an attractive strategy for safely treating resistant
gliomas.