CTDSP1 inhibitor rabeprazole regulates DNA-PKcs dependent topoisomerase I degradation and irinotecan drug resistance in colorectal cancer

• DOI: 10.1371/journal.pone.0228002
• Publication Date: 2020-08-07T22:03:59Z
• Authors: Hiroya Matsuoka; Koji Ando; Emma J. Swayze; Elizabeth C. Unan; Joseph Mathew; Quingjiang Hu; Yasuo Tsuda; Yuichiro Nakashima; Hiroshi Saeki; Eiji Oki; Ajit K. Bharti; Masaki Mori
• Keywords: Rabeprazole; Camptothecin; SN-38

Irinotecan specifically targets topoisomerase I (topoI), and is used to treat various solid tumors, but only 13–32% of patients respond the therapy. Now, it understood that rapid rate topoI degradation in response irinotecan causes resistance. We have published deregulated DNA-PKcs kinase cascade ensures at core drug resistance mechanism inhibitors, including irinotecan. also identified CTD small phosphatase 1 (CTDSP1) (a nuclear phosphatase) as a primary upstream regulator inhibitors. Previous reports showed rabeprazole, proton pump inhibitor (PPI) inhibits CTDSP1 activity. The purpose this study was confirm effects rabeprazole on activity its impact irinotecan-based therapy colon cancer. Using differentially expressing cells, we demonstrated contributes sensitivity by preventing degradation. Retrospective analysis receiving with or without has shown response. These results indicate promotes prevents effect, resulting To ensure best chance effective treatment, may not be suitable PPI for cancer treated