Like humans, canine companions spontaneously develop lymphomas that are treated by a cocktail of chemotherapy drugs. However, canines have high rates of developing multiple drug resistance (MDR), shortened clinical timelines and easy tumor accessibility, making them excellent models to study MDR mechanisms. Previously, we used in vitro cell models to demonstrate that metformin resensitized MDR cells to chemotherapy and prevented MDR development. Here, we used metformin to understand the in vivo molecular mechanisms regulating MDR development and reversal. Metformin was added to chemotherapy in MDR canines, reducing MDR biomarkers within all tumors tested, with one canine entering remission after prior repeated relapses. We employed microarray analyses to identify molecular networks involved in MDR development and the impact of metformin treatement. Tumor sampling throughout entry to remission and subsequent relapse allowed correlation of gene expression profiles to MDR tumor behavior. We discovered that the Anaphase Promoting Complex (APC), a ubiquitin-ligase regulating cell cycle progression, was impaired in MDR samples. In vitro tests demonstrated that APC activation resensitized MDR cells to chemotherapy. The companion canine, therefore, is a powerful translational MDR model that has revealed the APC as an underlying cellular mechanism associated with treatment resistance, and a novel potential therapeutic target.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.