Designing and Developing S100P Inhibitor 5-methyl Cromolyn (C5OH) for Pancreatic Cancer Therapy
Menée à l'aide de modèles murins, cette étude évalue l'activité antitumorale d'un composé appelé C5OH, un analogue d'une molécule utilisée dans le traitement de l'allergie (cromolyn), pour le traitement d'un adénocarcinome canalaire du pancréas
We have previously shown that the anti-allergic drug cromolyn blocks S100P interaction with its receptor RAGE and improves gemcitabine effectiveness in pancreatic ductal adenocarcinoma (PDAC). However, the concentration required to achieve its effectiveness was high (100muM). In this current study, we designed and synthesized analogs of cromolyn and analyzed their effectiveness compared to the parent molecule. An ELISA was used to confirm the binding of S100P with RAGE and to test the effectiveness of the different analogs. Analog 5-methyl cromolyn (C5OH) blocked S100P binding as well as the increases in NFkappaB activity, cell growth and apoptosis normally caused by S100P. In vivo C5OH systemic delivery reduced NFkappaB activity to a greater extent than cromolyn and at ten times lesser dose (50mg vs 5mg). Treatment of mice bearing syngeneic PDAC tumors showed that C5OH treatment reduced both tumor growth and metastasis. C5OH treatment of nude mice bearing orthotopic highly aggressive pancreatic Mpanc96 cells, increased the overall animal survival. Therefore, the cromolyn analog, C5OH, was found to be more efficient and potent than cromolyn as a therapeutic for PDAC.
http://mct.aacrjournals.org/content/early/2013/01/09/1535-7163.MCT-12-0771.abstract