Chemosensitisation of cancer cells by KU-0060648; a dual inhibitor of DNA-PK and PI-3K
Menée sur des lignées cellulaires de cancers du sein et du côlon, ainsi qu'à l'aide de xénogreffes, cette étude évalue la capacité d'un composé appelé KU-0060648, un inhibiteur dual de DNA-PK et PI-3K, à augmenter la cytoxicité de l'étoposide et de la doxorubiciine
DNA double strand breaks (DSBs) are the most cytotoxic lesions induced by topoisomerase II poisons. Non-homologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-PK activity. DNA-PKcs is structurally similar to PI-3K, which promotes cell survival and proliferation and is up-regulated in many cancers. KU-0060648 is a dual inhibitor of DNA-PK and PI-3K in vitro. KU-0060648 was investigated in a panel of human breast and colon cancer cells. The compound inhibited cellular DNA-PK auto-phosphorylation with IC50 values of 0.019 µM (MCF7 cells) and 0.17 µM (SW620 cells), and PI-3K-mediated AKT phosphorylation with IC50 values of 0.039 µM (MCF7 cells) and > 10 µM (SW620 cells). 5-day exposure to 1 µM KU-0060648 inhibited cell proliferation by > 95% in MCF7 cells, but only by 55% in SW620 cells. In clonogenic survival assays, KU-0060648 increased the cytotoxicity of etoposide and doxorubicin across the panel of DNA-PKcs-proficient cells, but not in DNA-PKcs-deficient cells, thus confirming that enhanced cytotoxicity was due to DNA-PK inhibition. In mice bearing SW620 and MCF7 xenografts, concentrations of KU-0060648 that were sufficient for in vitro growth inhibition and chemosensitisation were maintained within the tumour for at least 4 hours at non-toxic doses. KU-0060648 alone delayed the growth of MCF7 xenografts and increased etoposide-induced tumour growth delay in both in SW620 and MCF7 xenografts by up to 4.5-fold, without exacerbating etoposide toxicity to unacceptable levels. The proof of principle in vitro and in vivo chemosensitisation with KU-0060648 justifies further evaluation of dual DNA-PK and PI-3K inhibitors.
http://mct.aacrjournals.org/content/early/2012/05/10/1535-7163.MCT-11-0535.abstract