Vosaroxin is a
quinolone-derivative
anticancer agent with inhibitory activity on
type II DNA topoisomerases (TOP2). The aim of the present study was to investigate its cytotoxic effect and potential molecular mechanisms in human
cervical cancer HeLa cells.
Vosaroxin decreased cell viability and increased
lactate dehydrogenase (LDH) release in a dose- and time-dependent manner in HeLa cells, but not in normal cervical epithelial cells.
Vosaroxin also induced apoptosis and increased
caspase-3 activity in HeLa cells. These effects were accompanied by increased mitochondrial
reactive oxygen species (ROS) generation, lipid peroxidation, mitochondrial swelling and reduced
ATP production. Western blot analysis showed that
vosaroxin significantly reduced
hypoxia-inducible factor 1α (HIF-1α)
protein levels. However, it had no effect on HIF-1α protein degradation and HIF-1α
mRNA levels. The results showed that
vosaroxin inhibited the synthesis of HIF-1α
protein and interfered with the dimerization of HIF-1α and
aryl hydrocarbon receptor nuclear translocator (ARNT). In addition,
vosaroxin stimulated mitochondrial
enzyme activities and
superoxide dismutase 2 (SOD2) deacetylation via activating (Sir2 like
protein 3)
Sirt3. More importantly,
vosaroxin-induced inhibition on HIF-1α and its cytotoxic effects, as measured by cell viability, LDH release and apoptosis, were partially prevented by
Sirt3 knockdown or the
AMP-activated protein kinase (
AMPK) inhibitor compound C. Overall,
vosaroxin is demonstrated to be a chemotherapeutic agent targeting the
Sirt3/HIF-1 pathway and could be beneficial for inducing cytotoxicity in human
cervical cancer cells.