Glioblastoma multiforme (GBM) is a highly aggressive malignant
brain tumor. Despite some recent improvement in the treatment of this
malignancy, life expectancy of GBM patients remains extremely low. Therefore, continuous efforts to develop new treatment modalities are mandatory. A novel approach to
cancer treatment is the use of targeted treatments, alone and in combination with other
therapies. In this study, we evaluated the effects of novel combinations of conventional anti-
cancer treatments (
temozolomide or irradiation) with the targeted drug,
imatinib, or with
psychotropic drugs, belonging to the
selective serotonin reuptake inhibitors (
SSRIs) and
phenothiazine subclasses, as well as combination of
imatinib with psychotropic agents, on a human U87
glioblastoma cell line. The combination of
temozolomide with
imatinib or the
psychotropic drugs resulted in an additive anti-proliferative effect, while the combination of irradiation and the psychotropic agents resulted in a less than additive effect on cell proliferation. A marked synergistic anti-proliferative effect of
imatinib combined with the
psychotropic drugs fluoxetine,
sertraline or
perphenazine was demonstrated. None of the single or combined treatments led to a reduction in the expression of phosphorylated MAP
kinase. However, a marked synergistic reduction in the expression of the key regulatory molecule, pAKT, was detected, following the combined treatment of the cells with the
imatinib/psychotropics combination. This down-regulation of pAKT may mediate the synergistic anti-proliferative interaction of
imatinib with the psychotropic agents. Although the concentrations of the psychotropic agents used in this and other in vitro studies were beyond the clinically relevant blood levels in humans, recent studies have demonstrated anti-proliferative effects in vivo, using
sertraline in a human
colon cancer model. Thus, it seems that further in vivo studies combining
imatinib with psychotropic agents, especially
fluoxetine and
sertraline, are warranted.