Aurora kinase B/C inhibition impairs malignant glioma growth in vivo

摘要

Inhibition of Aurora kinase B has been evaluated as a therapy to block solid tumor growth in breast cancer, hepatocellular carcinoma, lung adenocarcinoma, and colorectal cancer models. Aurora kinase inhibitors are in early clinical trials for the treatment of leukemia. We hypothesized that Aurora B inhibition would reduce malignant glioma cell viability and result in impaired tumor growth in vivo. Aurora B expression is greater in cultured malignant glioma U251 cells compared to proliferating normal human astrocytes, and expression is maintained in U251 flank xenografts. Aurora B inhibition with AZD1152-HQPA blocked cell division in four different p53-mutant glioma cell lines (U251, T98G, U373, and U118). AZD1152-HQPA also inhibited Aurora C activation loop threonine autophosphorylation at the effective antiproliferative concentrations in vitro. Reduction in cell viability of U251 (p53R273H) cells was secondary to cytokinesis blockade and apoptosis induction following endoreplication. AZD1152-HQPA inhibited the growth of U251 tumor xenografts and resulted in an increase in tumor cell apoptosis both in vitro and in vivo. Subcutaneous administration of AZD1152-HQPA (25 mg/kg/day × 4 days; 2 cycles spaced 7 days apart) resulted in a prolongation in median survival after intracranial inoculation of U251 cells in mice (P = 0.025). This is the first demonstration that an Aurora kinase inhibitor can inhibit malignant glioma growth in vivo at drug doses that are clinically relevant.