Roscovitine effectively enhances antitumor activity of temozolomide in vitro and in vivo mediated by increased autophagy and Caspase-3 dependent apoptosis

Abstract

Gliomas are incurable solid tumors with extremely high relapse rate and definite mortality. As gliomas readily acquire resistance to only approved drug, temozolomide (TMZ), there is increasing need to overcome drug resistance by novel therapeutics or by repurposing the existing therapy. In the current study, we investigated antitumor efficacy of roscovitine, a Cdk inhibitor, in combination with TMZ in vitro (U87, U373, LN 18 and C6 cell lines) and in vivo (orthotopic glioma model in Wistar rats) glioma models. We observed that TMZ treatment following a pre-treatment with RSV significantly enhanced chemo-sensitivity and suppressed the growth of glioma cells by reducing Cdk-5 activity and simultaneous induction of autophagy and Caspase-3 mediated apoptosis. Additionally, reduced expression of Ki67, GFAP and markers of angiogenesis (CD31, VEGF) was observed in case of TMZ + RSV treatments. Also, presence of reactive astrocytes in peri-tumoral areas and in areas around blood vessels was completely diminished in TMZ + RSV treated brain sections. Taken together, results in the current study provide evidence that RSV in conjunction with TMZ restricts glioma growth, reduces angiogenesis and also eliminates reactive astrocytes thereby preventing the spread of glioma to adjacent healthy brain tissues and thus might be more potent therapeutic option for glioma.