VARDENAFIL MARKEDLY SUPPRESSES TUMOR GROWTH AND ENHANCES IDARUBICIN-INDUCED ANTITUMOR EFFECTS AGAINST GLIOMA IN VIVO
Idarubicin (IDA) is highly potent anticancer against glioma in vitro but not in vivo. Phosphodiesterase (PDE-5) hydrolyses cyclic guanosine monophosphate (cGMP), and is highly expressed in glioma. We proposed that increasing cGMP in the brain by the PDE-5 inhibitor vardenafil (VAR) augments IDA anti-glioma activity. We show that VAR (10 mg/kg) enhanced IDA (0.1mg/kg)-induced tumor growth-inhibitory activity and augmented IDAinduced improvement of survival against rat C6 glioma. Real time PCR results demonstrated that VAR inhibited mRNA expression of PDE-5 in the brains of animals treated with VAR, compared to control-treated group, implicating an important role for the inhibition of PDE-5 in VAR antitumor activity. Animals receiving either VAR alone or VAR+IDA improved survival when compared with control (PBS) or IDA groups. We examined the antiproliferative, pro-apoptotic and anti-invasive activities VAR in vitro and showed that VAR inhibited the growth and promoted apoptosis of rat C6 glioma cells. VAR also inhibited the migration and anchorage-independent growth of C6 cell. This suggests that the enhanced antitumor effect of VAR could be due to combined antiproliferative, pro-apoptotic and antiinvasive activities.