Abstract
Irinotecan is a strong anticancer drug whose mechanism of action has been reported only for the inhibition of DNA topoisomerase I (Topo I) through its active metabolite SN-38. In this study, we present a new mechanism of Irinotecan which inhibits the activities of MDM2, an E3 ligase of tumour suppressor p53, and Bcl-xL, an anti-apoptotic protein, through direct binding. In our structure modelling study, Irinotecan could fit to the binding sites of MDM2 and Bcl-xL for their known drugs, Nutlin-3 and ABT-737, with a betterbinding affinity than to Topo I. The direct binding of Irinotecan to both proteins was confirmed through a NMR study. We further showed that Irinotecan increased the amount of p53 only in the presence of MDM2 and inhibited the physical interaction of Bcl-xL with Bim, a core pro-apoptotic protein. In addition, we demonstrated that Irinotecan induced the down regulation of proliferation and strong G2/M arrest in HCT116 colon cancer cells shortly after treatment. Collectively, we suggest a new mechanism of action for Irinotecan as a dual target inhibitor of MDM2 and Bcl-xL facilitating the anticancer activities mediated by p53 and Bcl-xL interaction partners.
Keywords
Irinotecan
Dual-targets
MDM2
Bcl-xL
Structure modelling
NMR
… 5a medium supplemented with 2 mM Glutamine, 1% penicillin-streptomycin,
and 10% Fetal Bovine Serum at 37 °C with 5% CO 2 . SW480 cells were
cultured in L-15 medium in the same environment without CO 2 . Irinotecan Hydrochloride was purchased from Chengdu Biopurify Phytochemicals Ltd., Sichuan,China.…
