RT Journal Article
SR Electronic
T1 Delanzomib Interacts with Ritonavir Synergistically to Cause Endoplasmic Reticulum Stress in Renal Cancer Cells
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 3493
OP 3500
DO 10.21873/anticanres.12620
VO 38
IS 6
A1 MAKOTO ISONO
A1 AKINORI SATO
A1 TAKAKO ASANO
A1 KAZUKI OKUBO
A1 TOMOHIKO ASANO
YR 2018
UL http://ar.iiarjournals.org/content/38/6/3493.abstract
AB 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.