Quinacrine synergistically enhances the antivascular and antitumor efficacy of cediranib in intracranial mouse glioma

Abstract

Despite malignant glioma vascularity, anti-angiogenic therapy is largely ineffective. We hypothesize that efficacy of the antiangiogenic agent cediranib is synergistically enhanced in intracranial glioma via combination with the late-stage autophagy inhibitor quinacrine. Relative cerebral blood flow and volume (rCBF, rCBV), vascular permeability (K(trans)), and tumor volume were assessed in intracranial 4C8 mouse glioma using a dual-bolus perfusion MRI approach. Tumor necrosis and tumor mean vessel density (MVD) were assessed immunohistologically. Autophagic vacuole accumulation and apoptosis were assessed via Western blot in 4C8 glioma in vitro. Cediranib or quinacrine treatment alone did not alter tumor growth. Survival was only marginally improved by cediranib and unchanged by quinacrine. In contrast, combined cediranib/quinacrine reduced tumor growth by >2-fold (P < .05) and increased median survival by >2-fold, compared with untreated controls (P < .05). Cediranib or quinacrine treatment alone did not significantly alter mean tumor rCBF or K(trans) compared with untreated controls, while combined cediranib/quinacrine substantially reduced both (P < .05), indicating potent tumor devascularization. MVD and necrosis were unchanged by cediranib or quinacrine treatment. In contrast, MVD was reduced by nearly 2-fold (P < .01), and necrosis increased by 3-fold (P < .05, one-tailed), in cediranib + quinacrine treated vs untreated groups. Autophagic vacuole accumulation was induced by cediranib and quinacrine in vitro. Combined cediranib/quinacrine treatment under hypoxic conditions induced further accumulation and apoptosis. Combined cediranib/quinacrine treatment synergistically increased antivascular/antitumor efficacy in intracranial 4C8 mouse glioma, suggesting a promising and facile treatment strategy for malignant glioma. Modulations in the autophagic pathway may play a role in the increased efficacy.