Glioblastoma multiforme is the most aggressive brain tumor, and human
T98G cells constitute a useful glioblastoma multiforme model to
evaluate the 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
[LDs]) and compared it with the proteasome inhibitor Bortezomib
treatment. SR9009-treated cells exhibited significant reduction in
cell viability with consequences on cell cycle progression.
Dexamethasone synchronized cells displayed differential time responses
to SR9009 treatment with highest responses 18 to 30 h after
synchronization. SR9009 treatment decreased ROS levels while
Bortezomib increased them. However, both treatments significantly
increased LD levels, whereas the combined treatment showed additive or
synergistic effects 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.
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