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.
Highlights
Glioblastomas (GBM) comprise majority of malignant central nervous system tumors, with an annual incidence of 3.19 per 100,000 in the United States and a post-diagnosis 5-year survival rate of less than 5%1
Drug resistance is a major challenge for patients undergoing chemotherapy with TMZ
RSV was selected in the current study based on following considerations (1) Several preclinical and clinical studies suggest that RSV is well tolerated oral agent with therapeutic potential against a range of tumor types[7,9]
Summary
Glioblastomas (GBM) comprise majority of malignant central nervous system tumors, with an annual incidence of 3.19 per 100,000 in the United States and a post-diagnosis 5-year survival rate of less than 5%1. It remains one of the most aggressive solid tumors and is highly resistant to conventional chemotherapy incurring a high relapse rate with a meager mean life expectancy of less than 14 months in afflicted individuals[2]. We observed that the anti-proliferative effect of TMZ + RSV on glioma was partly mediated by Cdk[5] inhibition induced autophagy in conjunction with Caspase-3 mediated apoptosis, as evidenced by an increased expression of autophagy and apoptosis markers and increased survival upon pretreatment with 3-methyladenine (3-MA, early stage autophagy inhibitor) and Z-DEVD FMK, a Caspase-3 inhibitor
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