The membrane targeted apoptosis modulators erucylphosphocholine and erucylphosphohomocholine increase the radiation response of human glioblastoma cell lines in vitro

Background: Alkylphosphocholines constitute a novel class of
antineoplastic synthetic phospholipid derivatives that induce
apoptosis of human tumor cell lines by targeting cellular
membranes. We could recently show that the first intravenously
applicable alkylphosphocholine erucylphosphocholine (ErPC) is a
potent inducer of apoptosis in highly resistant human
astrocytoma/glioblastoma cell lines in vitro. ErPC was shown to
cross the blood brain barrier upon repeated intravenous injections
in rats and thus constitutes a promising candidate for glioblastoma
therapy. Aim of the present study was to analyze putative
beneficial effects of ErPC and its clinically more advanced
derivative erucylphosphohomocholine (erucyl-N, N,
N-trimethylpropanolaminphosphate, ErPC3, Erufosine (TM) on
radiation-induced apoptosis and eradication of clonogenic tumor
cells in human astrocytoma/glioblastoma cell lines in vitro.
Results: While all cell lines showed high intrinsic resistance
against radiation-induced apoptosis as determined by fluorescence
microscopy, treatment with ErPC and ErPC3 strongly increased
sensitivity of the cells to radiation-induced cell death (apoptosis
and necrosis). T98G cells were most responsive to the combined
treatment revealing highly synergistic effects while A172 showed
mostly additive to synergistic effects, and U87MG cells
sub-additive, additive or synergistic effects, depending on the
respective radiation-dose, drug-concentration and treatment time.
Combined treatment enhanced therapy-induced damage of the
mitochondria and caspase-activation. Importantly, combined
treatment also increased radiation-induced eradication of
clonogenic T98G cells as determined by standard colony formation
assays. Conclusion: Our observations make the combined treatment
with ionizing radiation and the membrane targeted apoptosis
modulators ErPC and ErPC3 a promising approach for the treatment of
patients suffering from malignant glioma. The use of this
innovative treatment concept in an in vivo xenograft setting is
under current investigation.