Fluvastatin potentiates anticancer activity of vorinostat in renal cancer cells

Abstract

Drug repositioning is an emerging approach to developing novel cancer treatments. Vorinostat is a histone deacetylase inhibitor approved for cancer treatment, but it could attenuate its anticancer activity by activating the mTOR pathway. The HMG‐CoA reductase inhibitor fluvastatin reportedly activates the mTOR inhibitor AMP‐activated protein kinase (AMPK), and we thought that it would potentiate vorinostat's anticancer activity in renal cancer cells. The combination of vorinostat and fluvastatin induced robust apoptosis and inhibited renal cancer growth effectively both in vitro and in vivo. Vorinostat activated the mTOR pathway, as evidenced by the phosphorylation of ribosomal protein S6, and fluvastatin inhibited this phosphorylation by activating AMPK. Fluvastatin also enhanced vorinostat‐induced histone acetylation. Furthermore, the combination induced endoplasmic reticulum (ER) stress that was accompanied by aggresome formation. We also found that there was a positive feedback cycle among AMPK activation, histone acetylation, and ER stress induction. This is the first study to report the beneficial combined effect of vorinostat and fluvastatin in cancer cells.

Simvastatin-Romidepsin Combination Kills Bladder Cancer Cells Synergistically

“…In the present study, inhibition of ER stress by cycloheximide markedly impaired the combination's ability to cause histone acetylation and induce apoptosis, suggesting that the ER stress induction played a pivotal role in the combination's action. This ER stress-histone acetylation sequence is also consistent with our previous results that there is a crosstalk between histone acetylation and ER stress induction [29,30,73,74,80]. The decreased expression of HDACs is thought to be a consequence of the ER stress induction according to the previous studies [29,30,73,74,80].…”

“…Unexpectedly, the simvastatin-induced AMPK activation was further promoted by romidepsin, which might also play a role in enhancing the histone acetylation. This AMPK activation was thought to be due to ER stress induction by the combination because the ER stressor tunicamycin increased the expression of AMPK, which is consistent with the previous reports [29,30,73,74]. ER stress is caused by the accumulation and aggregation of unfolded proteins [75], and excessive ER stress causes apoptosis and kills cancer cells [76][77][78].…”

“…2h). Our previous studies showed that ER stress activates AMPK [29,30], so we thought that the combination of romidepsin and simvastatin would also induce ER stress and thereby enhance AMPK activation. As expected, the combination induced ER stress cooperatively (Fig.…”

“…AMPK is a molecule which controls cellular energy homeostasis and metabolism essential for cancer proliferation [65,66] and therefore its activation is considered to be a novel anticancer mechanism [2][3][4][5]. Several studies demonstrated that simvastatin inhibits tumor growth by activating AMPK [12][13][14], and AMPK activation has been shown to induce histone acetylation [27][28][29][30]. We therefore thought that combining simvastatin with an HDAC inhibitor would kill cancer cells effectively by inducing histone acetylation cooperatively.…”

“…We thought that simvastatin would activate AMPK and the simvastatin-romidepsin combination would kill bladder cancer cells effectively by inducing histone cooperatively. We also investigated the role of endoplasmic reticulum (ER) stress induction in the combination's anticancer activity because histone acetylation is closely related to ER stress induction [29,30]. Furthermore, simvastatin is known to activate peroxisome proliferator-activated receptor (PPAR) γ, a regulator of fatty acid storage and glucose metabolism [31][32][33], which plays a crucial role in bladder cancer proliferation [34][35][36].…”