Abstract
Gliomas are the most common glial neoplasms, accounting for nearly 70% of
all primary brain tumours. The progression of low-grade gliomas into more
aggressive tumours is supported by the abnormal function of several
proto-oncogenes, including growth factor receptor tyrosine kinases
(GFR-TKs). In paper I, we showed that the pharmacologic inhibition (using
small molecule inhibitors) of IGF-1R, PDGFR and their intracellular
signalling via PI3-K and ERK1/2 kinases had only modest or not antitumour
activity in five glioblastoma cell lines (MO59J, MO59K, 8, 18 and 38).
The ability of the ionizing radiation to improve the effect of the
molecular targeted therapy was also investigated. Interaction between
small inhibitors and ionizing radiation was mostly additive or
subadditive, synergistic interaction was found in few analysed
combinations. One explanation may be the interaction of the IGF-1R with
PDGFR in maintenance the intracellular signalling activated. Therefore, a
therapeutic strategy of co-targeting both IGF-1R and PDGFR has been taken
into account. In two glioblastoma cell lines (18 and 38), we found that
dual targeting of IGF-1R and PDGFR increased cell death in comparison to
the inhibition of either receptor alone. In addition, co-inhibition of
IGF-1R and PDGFR increased radiosensitivity in 18 cells but failed to
intensify the effect of radiation in 38 cells. In glioblastoma cells,
radiation induced cell death has been connected to the activation of
c-Jun-NH2-terminal kinase-1 (JNK1). We found that JNK1 was weakly
expressed in 38 cells while it had an elevated expression in 18 cells.
Exposure to ionizing radiation induced JNK1 activation in 18 cells only,
suggesting that in this cell line radiation-activated JNK1 may provide an
anti-proliferative signalling parallel to receptors co-targeting. To test
this hypothesis, glioblastoma cells were treated with dominant negative
JNK1 (dnJNK1) and the response to radiation was assayed in the presence
or absence of receptors co-inhibition. Indeed, dnJNK1 protected 18 cells
against ×-radiation induced cell death. The dnJNK1 treatment did not
influence radiation response of the 38 cell line, which expressed low
levels of JNK1 (paper II). In conclusion, the combination of different
targeted agents, or targeted agents and radiotherapy, seems to be a
better treatment option than single agent therapy, with respect to the
evident molecular heterogeneity of brain tumours. Nevertheless, a detail
molecular understanding of the molecular pathogenesis of malignant
gliomas is necessary to design an effective therapy against this stage of
the disease.
