Fluvastatin potentiates anticancer activity of vorinostat in renal cancer cells

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Drug repositioning offers novel therapeutic strategies for cancer.
• Vorinostat, a histone deacetylase inhibitor, can activate the mTOR pathway, potentially limiting its efficacy.
• Fluvastatin, an HMG-CoA reductase inhibitor, activates AMP-activated protein kinase (AMPK), an mTOR inhibitor.

Purpose of the Study:

• To investigate the combined effect of vorinostat and fluvastatin on renal cancer cells.
• To determine if fluvastatin can potentiate vorinostat's anticancer activity by inhibiting the mTOR pathway.

Main Methods:

• In vitro and in vivo studies using renal cancer models.
• Assessment of apoptosis, cell growth, mTOR pathway activation (S6 phosphorylation), AMPK activation, histone acetylation, and endoplasmic reticulum (ER) stress.

Main Results:

• The combination of vorinostat and fluvastatin effectively inhibited renal cancer growth and induced apoptosis.
• Fluvastatin inhibited vorinostat-induced mTOR activation by activating AMPK.
• The combination enhanced vorinostat-induced histone acetylation and induced ER stress with aggresome formation.
• A positive feedback loop was identified involving AMPK activation, histone acetylation, and ER stress.

Conclusions:

• Vorinostat and fluvastatin exhibit a synergistic anticancer effect in renal cancer.
• This combination therapy represents a novel approach by modulating AMPK, histone acetylation, and ER stress pathways.
• This study is the first to demonstrate the beneficial combined effect of vorinostat and fluvastatin in cancer treatment.