A novel mechanism of irinotecan targeting MDM2 and Bcl-xL

Cited 0 time in scopus
Metadata Downloads
Title
A novel mechanism of irinotecan targeting MDM2 and Bcl-xL
Author(s)
B Lee; Jeong A Min; A Nashed; Sang-Ok Lee; J C Yoo; Seung-Wook Chi; G S Yi
Bibliographic Citation
Biochemical and Biophysical Research Communications, vol. 514, no. 2, pp. 518-523
Publication Year
2019
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 better binding 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.
Keyword
IrinotecanDual-targetsMDM2Bcl-xLStructure modellingNMR
ISSN
0006-291X
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.bbrc.2019.04.009
Type
Article
Appears in Collections:
Division of Biomedical Research > 1. Journal Articles
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.