Delanzomib Interacts with Ritonavir Synergistically to Cause Endoplasmic Reticulum Stress in Renal Cancer Cells

• Published in: Anticancer research 2018-06, Vol.38 (6), p.3493-3500
• Main Authors: Isono, Makoto, Sato, Akinori, Asano, Takako, Okubo, Kazuki, Asano, Tomohiko
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Apoptosis - drug effects; Boronic Acids - administration & dosage; Boronic Acids - pharmacology; Cancer; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Cytochrome P-450 CYP3A Inhibitors - administration & dosage; Cytochrome P-450 CYP3A Inhibitors - pharmacology; Drug Synergism; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; HIV; Human immunodeficiency virus; Humans; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kidneys; Male; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Protease inhibitors; Proteasome inhibitors; Proteasome Inhibitors - administration & dosage; Proteasome Inhibitors - pharmacology; Proteinase inhibitors; Rapamycin; Renal cell carcinoma; Ritonavir; Ritonavir - administration & dosage; Ritonavir - pharmacology; Stress; Stresses; Threonine - administration & dosage; Threonine - analogs & derivatives; Threonine - pharmacology; TOR protein; Tumor cell lines
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.12620

To investigate the efficacy against renal cancer cells of combining the HIV protease inhibitor ritonavir with the novel proteasome inhibitor delanzomib. Renal cancer cell lines 769-P, 786-O, Caki-2 and Renca were treated with ritonavir and delanzomib in vitro and in vivo, and the efficacy of combination was evaluated. The combination of ritonavir and delanzomib synergistically inhibited renal cancer growth and suppressed colony formation. It induced robust apoptosis evidenced by increased cell population in the sub-G fraction and increased number of annexin-V-positive cells. A 13-day treatment with the combination was well tolerated in the mouse model and inhibited tumor growth significantly. Mechanistically, the combination synergistically induced endoplasmic reticulum stress and inhibited the mammalian target of rapamycin (mTOR) pathway. The effectiveness of combination of ritonavir and delanzomib appears to be due to the induction of ER stress and inhibition of the mTOR pathway.