Paper Details
- Hyeon-Cheol Lee-Okada (Department of Biochemistry, Juntendo University Graduate School of Medicine / h-lee@juntendo.ac.jp)
1) Department of Gastroenterology and Minimally Invasive Surgery, Juntendo University Hospital , 2) Department of Gastroenterology Surgery, Shanghai East Hospital (East Hospital Affiliated to Tongji University), China , 3) Department of Biochemistry, Juntendo University Graduate School of Medicine , 4) Department of Molecular Pathogenesis, Juntendo University Graduate School of Medicine , 5) Human Genetics Laboratory, National Institute of Genetics
Irinotecan (camptothecin-11 [CPT-11]) is a topoisomerase I inhibitor that has been used in the treatment of a wide spectrum of cancers including gastric cancer. Recent reports suggest that the expression of CES2, a serine hydrolase that converts irinotecan to its active compound SN-38, is regulated by the tumor-suppressor p53. In this study, we investigated whether irinotecan acted synergistically with a p53 activator nutlin-3a in human gastric cancer cells. Nutlin-3a treatment enhanced the expression of CES2 in gastric cancer cell lines with wild-type p53. However, this effect was not observed in cells with non-functional p53. Irinotecan showed synergistic antitumor effects in combination with nutlin-3a in gastric cancer cells with wild-type p53, whereas the survival of cells with non-functional p53 was not significantly affected by the presence of nutlin-3a. These results provide evidence that p53 activation can enhance the antitumor effect of irinotecan or other anticancer prodrugs activated by CES2 in gastric cancer cells through upregulation of CES2 expression.
