טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentLevin Evgeny
SubjectRelevance of Peripheral Benzodiazepine Receptors to Brain
Cancer
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Moshe Gavish


Abstract

Benzodiazepines (Bzs) are a group of drugs used clinically as anxiolytics, sedatives, anticonvulsants and muscle relaxants. Their therapeutic effects have been correlated with their potency in binding to central benzodiazepine receptors in the central nervous system. In addition to central-type benzodiazepine receptors (CBR), benzodiazepines also bind to receptors located in various peripheral organs as well as in brain glial cells. These receptors are called "peripheral-type benzodiazepine receptors" (PBR). The aim of the present study was to examine any putative involvement of PBR in brain cancer. As a model, we used glioma cell lines from different origins. In the current study, we found that untreated cells with relatively high PBR densities display a relatively more aggressive malignant phenotype.  Moreover this increased malignancy was associated with higher proliferation rates and less apoptosis than cells with low PBR densities. Upon stable antisense knockout of the 18-kDa IBP subunit of the PBR in C6 rat glioma cells, we found that the IBP antisense clones, which have reduced PBR density, display a more aggressive transformed phenotype. Again, this more aggressive phenotype is associated with higher proliferation rates and lower apoptosis than control cells. Our study suggests that levels of malignancy, including increased proliferation rates, result in increased PBR densities. Our knockout studies indicate that PBR serve to reduce proliferation rates in cancer cells. However, an uncoupling between PBR density and proliferation rate appear to occur i.e. PBR regulation no longer is able to keep up with the pathological proliferation rates.  The effectiveness of PBR control in cancer cells determines the level of malignancy.