Apoptotic effect of atorvastatin in glioblastoma spheroids tumor cultured in fibrin gel.

Abstract

Glioblastoma multiform (GBM) is one of the most common and highly aggressive primary brain tumors that thought to be of glial cells origin. The new available therapy for glioblastoma is based on better understanding of molecular malignant progression in this tumor. It is better to identify key molecular targets stimulating signaling pathways that lead to initiation of apoptosis for treatment of glioblastoma. Tumorigenesis broadly is controlled by tumor microenvironment and design of best biomimetic culture systems dependency on these conditions allow for in vitro and in vivo tumor modeling for studies of cancer cells behavior to drugs. We engineered three-dimensional (3D) human tumor models using U87 glioma cells in fibrin gel that mimic microenvironmental feature of glioblastoma in vivo. In this study, atorvastatin was used as a kind of statins for induction of apoptosis, and inhibition of migration and invasion in glioma cells. To reach for these aims, 3D model of glioma in fibrin gel was used with different concentrations of atorvastatin (1, 5, 10μM) to assay apoptotic genes expression by real time PCR and Tunel assay. After 24 and 48h exposing with different concentrations of atorvastatin, cell migration and invasion of tumor cells were investigated. The results showed atorvastatin induced apoptosis of glioma spheroids dose- dependently. The most likely mechanisms are the induction of apoptosis by caspase-8- caspase-3 signaling pathway. The invasion and migration of U87 spheroid cells decreased after 48h especially with 10μM concentration of atorvastatin. Finally these results suggest that this biomimetic model with fibrin may provide a vastly applicable 3D culture system to study the effect of anti-cancer drugs such as atrovastatin on tumor malignancy in vitro and in vivo and atorvastatin could be used as anticancer agent for glioblastoma treatment.