Simvastatin-romidepsin combination kills bladder cancer cells synergistically

The HMG-CoA reductase inhibitor simvastatin activates AMP-activated protein kinase (AMPK) and thereby induces histone acetylation. We postulated that combining with the deacetylase (HDAC) romidepsin would kill bladder cancer cells by inducing acetylation cooperatively. combination of induced robust apoptosis killed synergistically. In murine subcutaneous tumor models using MBT-2 cells, a 15-day treatment 0.5 mg/kg 15 was well tolerated inhibited growth significantly. Mechanistically, activating AMPK. also decreased expression HDACs, thus further promoting This AMPK activation essential for combination's action because compound C, an inhibitor, suppressed combination-induced ability to induce apoptosis. found increased peroxisome proliferator-activated receptor (PPAR) γ, leading reactive oxygen species production. Furthermore, endoplasmic reticulum (ER) stress this ER shown be associated acetylation, playing important role in action. Our study suggests there is positive feedback cycle between induction PPARγ expression.