In vitro apoptotic induction of human glioblastoma cells by Fas ligand plus etoposide and in vivo antitumour activity of combined drugs in xenografted nude rats
Résumé
Human glioblastomas that express Fas/CD95 receptor are highly resistant to conventional brain tumour therapies. The aim of this study is to evaluate anti-tumour properties of a combination of Fas ligand (FasL) plus etoposide with or without dexamethasone on intracerebral experimental glioblastomas. The human Fas-expressing glioblastoma cell line, U-87 MG, was firstly studied in vitro for apoptosis and proliferation assays in the presence of FasL and etoposide, separately or associated, in order to detect a supra-additive effect on FasL or etoposide-induced apoptosis. The tumourigenicity of the U-87 MG cell line and therapeutic effects of FasL-etoposide alone or combined with dexamethasone were next studied on U-87 MG cells xenografted to nude-rat brain and tumour size was hence examined by histological and immunohistochemical stainings. We demonstrated in vitro that the combination of both molecules strongly inhibited the proliferation rate and increased the sensitivity of glioblastoma cells to Fas or etoposide-mediated apoptosis. Moreover, analysis of rat brains was performed 30 days after xenograft of glioblastoma cells. These data show that the combination of FasL and etoposide could reduce significantly the tumour size and that the addition of dexamethasone enhanced the inhibiting effect of FasL and etoposide on tumour growth in vivo.