Drug screening in human physiologic medium identifies uric acid as an inhibitor of rigosertib efficacy.

Autor: Rawat V; Department of Physiology and Biophysics, University of Illinois College of Medicine, University of Illinois Cancer Center, Chicago, Illinois, USA., DeLear P; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA., Prashanth P; Department of Physiology and Biophysics, University of Illinois College of Medicine, University of Illinois Cancer Center, Chicago, Illinois, USA., Ozgurses ME; Department of Physiology and Biophysics, University of Illinois College of Medicine, University of Illinois Cancer Center, Chicago, Illinois, USA., Tebeje A; Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Burns PA; Department of Physiology and Biophysics, University of Illinois College of Medicine, University of Illinois Cancer Center, Chicago, Illinois, USA., Conger KO; Department of Physiology and Biophysics, University of Illinois College of Medicine, University of Illinois Cancer Center, Chicago, Illinois, USA., Solís C; Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, Florida, USA., Hasnain Y; Department of Physiology and Biophysics, University of Illinois College of Medicine, University of Illinois Cancer Center, Chicago, Illinois, USA., Novikova A; Department of Physiology and Biophysics, University of Illinois College of Medicine, University of Illinois Cancer Center, Chicago, Illinois, USA., Endress JE; Meyer Cancer Center, Weill Cornell Medicine, New York, New York, USA., González-Sánchez P; Department of Metabolism and Physiology, Moffitt Cancer Center, Tampa, Florida, USA., Dong W; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Stephanopoulos G; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., DeNicola GM; Department of Metabolism and Physiology, Moffitt Cancer Center, Tampa, Florida, USA., Harris IS; Department of Biomedical Genetics, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA., Sept D; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA., Mason FM; Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Coloff JL; Department of Physiology and Biophysics, University of Illinois College of Medicine, University of Illinois Cancer Center, Chicago, Illinois, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2024 May 30; Vol. 9 (13). Date of Electronic Publication: 2024 May 30.
DOI: 10.1172/jci.insight.174329
Abstrakt: The nonphysiological nutrient levels found in traditional culture media have been shown to affect numerous aspects of cancer cell physiology, including how cells respond to certain therapeutic agents. Here, we comprehensively evaluated how physiological nutrient levels affect therapeutic response by performing drug screening in human plasma-like medium. We observed dramatic nutrient-dependent changes in sensitivity to a variety of FDA-approved and clinically trialed compounds, including rigosertib, an experimental cancer therapeutic that recently failed in phase III clinical trials. Mechanistically, we found that the ability of rigosertib to destabilize microtubules is strongly inhibited by the purine metabolism end product uric acid, which is uniquely abundant in humans relative to traditional in vitro and in vivo cancer models. These results demonstrate the broad and dramatic effects nutrient levels can have on drug response and how incorporation of human-specific physiological nutrient medium might help identify compounds whose efficacy could be influenced in humans.
Databáze: MEDLINE