Understanding the Effects of Rapamycin on Metabolic Pathways in Human Primary Adipocytes and Hepatocytes
Join Paula Lapinskas, Ph.D. Molecular Toxicology to discuss work performed while working at Signal Pharmaceuticals, LLC (a wholly-owned subsidiary of Celgene Corp.) in a discussion about the use of global biochemical profiling and its application in drug action and toxicology.
The study to be presented will highlight a metabolomic approach to understanding the metabolic effects of a drug (rapamycin), an mTOR signal transduction pathway inhibitor used in the treatment of several cancers. The studies were performed on cultured human hepatocytes and adipocytes. The Metabolon global biochemical profiling platform was utilized to identify dose- and time-dependent biochemical changes induced by the drug of interest. Among the metabolic changes that will be discussed are alterations in major energy pathways and insulin resistance in drug-treated cells. These biochemical findings correlate with changes reported in published literature using whole-body approaches, thereby adding validity to the results and additional weight to in vitro assays drug research.
Additionally, novel observations were also observed, including the induction of oxidative stress, providing additional insights into the mechanism of drug toxicity. This study was performed to validate the metabolomic approach and will be used to screen novel mTOR kinase inhibitors for purposes of market differentiation. Rapamycin is a mTOR, FRB protein domain binding protein/inhibitor which differs in action from kinase domain inhibitors, which may have less toxicity.
Additional thanks for the content of the presentation go to Celgene collaborators: Rupesh Amin, Dale Baker, Sabita Sanker and Deborah Mortensen.
