Ritonavir Interacts With Belinostat to Cause Endoplasmic Reticulum Stress and Histone Acetylation in Renal Cancer Cells

• Published in: Oncology research Vol. 24; no. 5; pp. 327 - 335
• Main Authors: Isono, Makoto, Sato, Akinori, Okubo, Kazuki, Asano, Takako, Asano, Tomohiko
• Format: Journal Article
• Language: English
• Published: Elmsford, NY Cognizant Communication Corporation 01.01.2016
• Subjects: Acetylation - drug effects; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Belinostat; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Drug Synergism; Endoplasmic Reticulum (er) Stress; Endoplasmic Reticulum Stress - drug effects; Histone Deacetylase Inhibitors - pharmacology; Histones - metabolism; Humans; Hydroxamic Acids - administration & dosage; Hydroxamic Acids - pharmacology; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Renal Cell Cancer; Ritonavir; Ritonavir - administration & dosage; Ritonavir - pharmacology; Sulfonamides - administration & dosage; Sulfonamides - pharmacology
• ISSN: 0965-0407; 1555-3906
• DOI: 10.3727/096504016X14666990347635

The histone deacetylase (HDAC) inhibitor belinostat increases the amount of unfolded proteins in cells by promoting the acetylation of heat shock protein 90 (HSP90), thereby disrupting its chaperone function. The human immunodeficiency virus protease inhibitor ritonavir, on the other hand, not only increases unfolded proteins by suppressing HSP90 but also acts as a proteasome inhibitor. We thought that belinostat and ritonavir together would induce endoplasmic reticulum (ER) stress and kill renal cancer cells effectively. The combination of belinostat and ritonavir induced drastic apoptosis and inhibited the growth of renal cancer cells synergistically. Mechanistically, the combination caused ER stress (evidenced by the increased expression of the ER stress markers) and also enhanced histone acetylation by decreasing the expression of HDACs. To our knowledge, this is the first study that showed a beneficial combined effect of belinostat and ritonavir in renal cancer cells, providing a framework for testing the combination in renal cancer patients.