TY - JOUR T1 - Delanzomib Interacts with Ritonavir Synergistically to Cause Endoplasmic Reticulum Stress in Renal Cancer Cells JF - Anticancer Research JO - Anticancer Res SP - 3493 LP - 3500 DO - 10.21873/anticanres.12620 VL - 38 IS - 6 AU - MAKOTO ISONO AU - AKINORI SATO AU - TAKAKO ASANO AU - KAZUKI OKUBO AU - TOMOHIKO ASANO Y1 - 2018/06/01 UR - http://ar.iiarjournals.org/content/38/6/3493.abstract N2 - Background/Aim: To investigate the efficacy against renal cancer cells of combining the HIV protease inhibitor ritonavir with the novel proteasome inhibitor delanzomib. Materials and Methods: 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. Results: 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-G1 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. Conclusion: The effectiveness of combination of ritonavir and delanzomib appears to be due to the induction of ER stress and inhibition of the mTOR pathway. ER -