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• W2090095628 abstract "You have accessJournal of UrologyBladder Cancer: Basic Research (I)1 Apr 2013593 RITONAVIR COMBINED WITH BORTEZOMIB SYNERGISTICALLY INDUCES ENDOPLASMIC RETICULUM STRESS AND UBIQUITINATED PROTEIN ACCUMULATION IN BLADDER CANCER CELLS Akinori Sato, Takako Asano, Keiichi Ito, and Tomohiko Asano Akinori SatoAkinori Sato Tokorozawa, Japan More articles by this author , Takako AsanoTakako Asano Tokorozawa, Japan More articles by this author , Keiichi ItoKeiichi Ito Tokorozawa, Japan More articles by this author , and Tomohiko AsanoTomohiko Asano Tokorozawa, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1989AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The HIV protease inhibitor ritonavir induces endoplasmic reticulum (ER) stress and acts against malignancies, and we hypothesized that inhibiting proteasome activity under ER stress would further inhibit cancer cell growth by enhancing protein ubiquitination. In the present study we found that the combination of ritonavir and the proteasome inhibitor bortezomib, both clinically available drugs, inhibits bladder cancer growth by enhancing ER stress and protein ubiquitination. METHODS The viability and clonogenicity of bladder cancer cells (T24, EJ, VmCub1) treated with ritonavir (25-50 μM) and/or bortezomib (5-10 nM) were assessed by MTS assay and colony formation assay. Combination indexes were calculated using the Chou-Talalay method. Induction of apoptosis and changes in cell cycle were evaluated by using flow cytometry. Induction of ER stress, protein ubiquitination, histone acetylation, and the expression of cyclin D1, cyclin-dependent kinase (CDK) 4, p21, and histone deacetylase (HDAC)-1, -2, -3, -6 were evaluated by western blot analysis. RESULTS Ritonavir and bortezomib induced drastic apoptosis (up to 17.2 fold annexin-V fluorescence intensity compared with control) and inhibited the growth of bladder cancer cells synergistically (combination indexes <1, n = 6). Colony formation was also suppressed significantly (P <0.05). The combination decreased the expression of cyclin D1 and CDK4 and increased the expression of p21, thus leading to the accumulation of the cells in the sub-G1 fraction. Mechanistically, the combination induced ER stress, as evidenced by the increased expression of glucose-regulated protein 78 and heat shock protein 70, and caused ubiquitinated protein accumulation synergistically: 10 nM bortezomib caused ER stress and ubiquitinated protein accumulation only when combined with 50 μM ritonavir. Interestingly, we found that the combination also enhanced histone acetylation synergistically by decreasing the expression of HDACs. This histone acetylation would be another important mechanism of action and is thought to have caused the increased p21 expression. CONCLUSIONS The combination of ritonavir and bortezomib induces apoptosis and inhibits the growth of bladder cancer cells by inducing ER stress and ubiquitinated protein accumulation. Histone acetylation is another important mechanism of the combination's tumor-toxic action. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e242-e243 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Akinori Sato Tokorozawa, Japan More articles by this author Takako Asano Tokorozawa, Japan More articles by this author Keiichi Ito Tokorozawa, Japan More articles by this author Tomohiko Asano Tokorozawa, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ..." @default.
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• W2090095628 title "593 RITONAVIR COMBINED WITH BORTEZOMIB SYNERGISTICALLY INDUCES ENDOPLASMIC RETICULUM STRESS AND UBIQUITINATED PROTEIN ACCUMULATION IN BLADDER CANCER CELLS" @default.
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