gms | German Medical Science

Objective: High level of fatty acid synthase (FAS) expression have been reported in different tumors, including prostate, breast and ovarian cancer, and its inhibition reduces tumor growth in vitro and in vivo. We showed increased FAS expression level in glioblastoma WHO grade IV compared to astrocytoma WHO grade I to III. To define the role of FAS in human glioblastoma growth control and as a possible new target in glioblastoma therapy we investigated the behavior of primary glioblastoma cell cultures under influence of different FAS inhibitors.

Methods: The primary glioblastoma cell cultures were established and maintained in our laboratory. For measurement of cell growth and apoptosis cells were incubated with Cerulenin (4, 20, 40 μM), C75 (4, 20, 40 μM), and Orlistat (100, 150, 200 μM) for 24-72 h. We analysed cell growth via viability (MTT reduction), proliferation (BrdU incorporation) and clonogenic survival (colony formation). Apoptosis was measured via nuclear fragmentation (Hoechst staining), PARP cleavage and Bcl-2 reduction (western blotting).

Results: The viability and proliferation assays showed for Cerulenin and C75 in a concentration of 40 μM and for Orlistat (200 μM) significantly reduced cell growth within 72h (p < 0.005). Incubation with all three inhibitors in their highest concentration resulted in reduced colony formation. We detected in all cell cultures strong nuclear fragmentation after 24h incubation with all 3 inhibitors. PARP-cleavage and Bcl-2 reduction as indicators for apoptosis were detected after 24h for all three inhibitors in their highest concentration.

Conclusions: We could demonstrate that treatment with the FAS inhibitors, Cerulenin, C75 and Orlistat significantly decreased glioblastoma cell growth in vitro. We also showed a strong nuclear fragmentation and PARP-cleavage as indicator for apoptosis. Our data suggest that FAS represents a novel possible target for antiglioma therapy. Further in vivo studies will confirm our recent findings.