Open AccessFluvastatin potentiates anticancer activity of vorinostat in renal cancer cells
Author(s) -
Okubo Kazuki,
Isono Makoto,
Miyai Kosuke,
Asano Takako,
Sato Akinori
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14225
Subject(s) - vorinostat , fluvastatin , histone deacetylase inhibitor , cancer research , histone deacetylase , ampk , pharmacology , pi3k/akt/mtor pathway , chemistry , kinase , protein kinase a , medicine , histone , signal transduction , biochemistry , gene , simvastatin
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.