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- W2325001609 abstract "You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III1 Apr 2016MP92-16 RITONAVIR AND DELANZOMIB INHIBIT RENAL CANCER GROWTH IN VITRO AND IN VIVO BY INDUCING ENDOPLASMIC RETICULUM STRESS SYNERGISTICALLY Makoto Isono, Akinori Sato, Kazuki Okubo, Takako Asano, Keiichi Ito, and Tomohiko Asano Makoto IsonoMakoto Isono More articles by this author , Akinori SatoAkinori Sato More articles by this author , Kazuki OkuboKazuki Okubo More articles by this author , Takako AsanoTakako Asano More articles by this author , Keiichi ItoKeiichi Ito More articles by this author , and Tomohiko AsanoTomohiko Asano More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2649AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Induction of endoplasmic reticulum (ER) stress is a novel strategy for treating malignancies. The human immunodeficiency virus (HIV) protease inhibitor ritonavir increases the amount of unfolded proteins by suppressing the heat shock protein 90. We thought that combining ritonavir with the proteasome inhibitor delanzomib would kill renal cancer cells effectively by inhibiting the degradation of these unfolded proteins and thereby inducing ER stress. METHODS Renal cancer cells (769-P, 786-O, Caki-2, Renca) were treated with ritonavir (25-50 µM) and/or delanzomib (25-50 nM). Cell viability and clonogenicity were assessed by MTS assay and colony formation assay. In vivo efficacy was evaluated using murine subcutaneous tumor models. Flow cytometry was used for cell cycle analysis and annexin-V assay. Western blotting was used to evaluate the induction of ER stress (expression of glucose-regulated protein 78, endoplasmic reticulum resident protein 44, and endoplasmic oxidoreductin-1-like protein) and histone acetylation, as well as the expression of Akt, cyclin D1, cyclin-dependent kinase (CDK) 4, sestrin 2, AMP-activated protein kinase (AMPK), and mammalian target of rapamycin (mTOR). RESULTS The combination of ritonavir and delanzomib inhibited renal cancer growth synergistically (combination indexes <1) and suppressed colony formation significantly (P <0.05). It decreased the expression of cyclin D1 and CDK4, leading to the accumulation of the cells in the sub-G1 fraction (up to 97.0%). The combination induced robust apoptosis (annexin-V positive cells increased up to 91.8%), and this apoptosis seemed to be caspase-dependent because the pancaspase inhibitor Z-VAD-FMK markedly decreased the number of the annexin-V positive cells. In murine tumor models, a 13-day treatment with 15 mg/kg ritonavir and 30 µg/kg delanzomib was well tolerated and inhibited tumor growth significantly (P = 0.009). As expected, the combination increased the expression of the ER stress markers synergistically. It also increased the expression of the mTOR inhibitors sestrin 2 and AMPK and decreased the expression of mTOR and Akt, confirming the mTOR pathway inhibition following the ER stress induction. Interestingly, we also found that the combination-induced ER stress enhanced histone acetylation synergistically. CONCLUSIONS Ritonavir and delanzomib together inhibit renal cancer growth by inducing ER stress synergistically. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1168 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Makoto Isono More articles by this author Akinori Sato More articles by this author Kazuki Okubo More articles by this author Takako Asano More articles by this author Keiichi Ito More articles by this author Tomohiko Asano More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ..." @default.
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- W2325001609 title "MP92-16 RITONAVIR AND DELANZOMIB INHIBIT RENAL CANCER GROWTH IN VITRO AND IN VIVO BY INDUCING ENDOPLASMIC RETICULUM STRESS SYNERGISTICALLY" @default.
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