Small molecule inhibitor YM155-mediated activation of death receptor 5 is crucial for chemotherapy-induced apoptosis in pancreatic carcinoma
Menée sur des lignées cellulaires et à l'aide de xénogreffes de cancer du pancréas, cette étude évalue les mécanismes liés à l'activité antitumorale d'un composé appelé YM155, développé initialement pour réduire l'expression de la survivine
Despite much effort, pancreatic cancer survival rates are still dismally low. Novel therapeutics may hold the key to improving survival. YM155 is a small molecule inhibitor which has shown anti-tumor activity in a number of cancers by reducing the expression of survivin. The aim of our study is to understand the mechanisms by which YM155 functions in pancreatic cancer cells. We established the anti-tumor effect of YM155 with in vitro studies in the cultured cells, and in vivo studies using a mouse xenograft model. Our data demonstrated that YM155 reduced the expression of survivin; however down-regulation of survivin itself is insufficient to induce apoptosis in pancreatic cancer cells. We showed for the first time that treatment with YM155 increased death receptor 5 (DR5) expression in pancreatic cancer cells. We found that YM155 induced apoptosis by broad-spectrum inhibition of IAP family member proteins (e.g. CIAP1/2 and FLIP) and induced pro-apoptotic Bak protein up-regulation and activation; the anti-tumor effect of YM155 treatment with either the DR5 agonist lexatumumab or gemcitabine on pancreatic cancer cells was synergistic. Our data also revealed that YM155 inhibit tumor growth in vivo, whilst had no apparent toxicity to the non-cancerous human pancreatic ductal epithelial cell line (HPDE). Together, these findings suggest that YM155 could be a novel therapeutic agent for pancreatic cancer.
http://mct.aacrjournals.org/content/early/2014/10/24/1535-7163.MCT-14-0229.abstract 2014