The chemotherapeutic effect of SR9009, a REV-ERB agonist, on the human glioblastoma T98G cells

MARIO E. GUIDO; PAULA M. WAGNER; NATALIA M MONJES

ASN Neuro

Sage journals

Año: 2019

1759-0914

Glioblastoma multiforme (GBM) is the most aggressive brain tumor and human T98G cells constitute a useful GBM model to evaluate chemotherapeutic agents. Modern life (shiftwork, jetlag, etc.) may cause circadian disorganization promoting higher cancer risk and metabolic disorders. Although little is known about the tumor-intrinsic circadian clock function, pharmacological modulation of circadian components may offer selective anticancer strategies. REV-ERBs are heme-binding circadian clock components acting as repressors of processes involved in tumorigenesis such as metabolism, proliferation and inflammation. A synthetic pyrrole derivative (SR9009) that acts as REV-ERBs specific agonists exhibits potent in vivo activity on metabolism and tumor cell viability. Here we investigated SR9009 effects on T98G cell viability, differential chemotherapy time responses and underlying metabolic processes (reactive oxygen species: ROS and lipid droplets: LD) and compared it with the proteasome inhibitor Bortezomib (BOR) treatment. SR9009-treated cells exhibited significant reduction in cell viability with consequences on cell cycle progression. Dexamethasone (DEX) synchronized cells displayed differential time responses to SR9009 treatment with highest responses 18-30 h after synchronization. SR9009 treatment decreased ROS levels while BOR increased them. However, both treatments significantly increased LD levels whereas the combined treatment showed synergism between both drugs. In addition, we extended these studies to HepG2 cells which also showed a significant decrease in cell viability and ROS levels, and the increase in LD levels after SR9009 treatment. Our results suggest that the pharmacological modulation of the tumor intrinsic clock by REV-ERB agonists severely affects cell metabolism and promotes cytotoxic effects on cancer cells.