Cilengitide is a cyclic peptide antagonist of integrins ab3 and ab5
which is currently evaluated as a novel therapeutic agent for recurrent and
newly diagnosed glioblastoma. Its mode of action is thought to be mainly
antiangiogenic, but may include direct effects on tumor cells, notably on
attachment, migration, invasion, and viability. Here we show that cilengitide
induces detachment in some glioma cell lines, while the effect on
cell viability is modest. Detachment induced by cilengitide could not be
predicted by the level of expression of the cilengitide target molecules at the
cell surface. Glioma cell death induced by cilengitide was associated with
the generation of caspase activity, but caspase activity was dispensable for
cell death since ectopic expression of cytokine response modifier (crm)-A
or the broad spectrum caspase inhibitor, zVAD-fmk, were not protective.
Moreover, forced expression of Bcl-XL or altering the p53 status did not
modulate cilengitide-induced cell death. No consistent effects of cilengitide
on glioma cell migration or invasiveness were observed in vitro. Neither
ectopic expression of MGMT in MGMT-negative cells nor silencing the
MGMT gene in MGMT-positive cells altered their response to cilengitide
alone or cilengitide in combination with temozolomide. These data
suggest that the beneficial clinical effects derived from cilengitide in vivo
may arise from altered perfusion that promotes temozolomide delivery to
glioma cells.