MP98-18 INHIBITION OF HSP90 SYNERGISTICALLY POTENTIATES ANTITUMOR EFFECT OF NVP-BEZ235 AND SATRAPLATIN COMBINATION THERAPY IN CISPLATIN-RESISTANT HUMAN BLADDER CANCER CELLS THROUGH THE DOWN-REGULATION OF AKT AND ERK SIGNALINGстатья из журнала
Аннотация: You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology V1 Apr 2017MP98-18 INHIBITION OF HSP90 SYNERGISTICALLY POTENTIATES ANTITUMOR EFFECT OF NVP-BEZ235 AND SATRAPLATIN COMBINATION THERAPY IN CISPLATIN-RESISTANT HUMAN BLADDER CANCER CELLS THROUGH THE DOWN-REGULATION OF AKT AND ERK SIGNALING Cheol Yong Yoon, Mi Kyung Gong, Dong Heok Kang, Myung Soo Kim, Won Sik Jung, Young Sik Kim, In Rae Cho, and Young Deuk Choi Cheol Yong YoonCheol Yong Yoon More articles by this author , Mi Kyung GongMi Kyung Gong More articles by this author , Dong Heok KangDong Heok Kang More articles by this author , Myung Soo KimMyung Soo Kim More articles by this author , Won Sik JungWon Sik Jung More articles by this author , Young Sik KimYoung Sik Kim More articles by this author , In Rae ChoIn Rae Cho More articles by this author , and Young Deuk ChoiYoung Deuk Choi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3083AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Here we report the role of HSP90 in platinum resistance in human bladder cancer cells and synergistic antitumor effect of HSP90 inhibition on the combination therapy of NVP-BEZ245 and platinum in cisplatin-resistant human bladder cancer cells. METHODS To evaluate differential gene expression according to different platinum sensitivity in human bladder cancer cells, we conducted microarray analysis-based gene expression profiling with cisplatin sensitive (T24) and resistant (T24R2) human bladder cancer cells and the results were validated by Western blot analysis. To test synergism between drugs combination index based on CCK-8 assay and also colony forming assay were used. To determine mechanisms underlying synergistic interaction between drugs, flow cytometry and Western blot analysis were performed. RESULTS Gene expression profiling showed that the expression of 5,021 and 1,727 genes had more than two-fold and four-fold changes between T24 and T24R2 cells after platinum treatment. Especially Hsp90 (HSP90AA1, HSP90AA2) and RAS-MEK-MAPK and PI3K-AKT-mTOR signaling pathways showed significantly different expressions in the two cell lines. The combination of NVP-BEZ235 and satraplatin showed strong synergistic antitumor effect in cisplatin-resistant T24R2 cells. However, we found that both NVP-BEZ235 monotherapy and combination treatment with satraplatin caused increased phosphorylation of MEK1/2 and ERK1/2 despite of the suppression of PI3K/AKT signaling in T24R2 cells. The addition of 17-DMAG, HSP90 inhibitor to NVP-BEZ235 and satraplatin combination therapy down regulated both AKT and ERK signaling and synergistically enhanced antitumor effect in T24R2 cells through the caspase-dependent apoptosis and phase-specific cell cycle arrest. CONCLUSIONS The present study demonstrated that HSP90 plays important role for the platinum resistance in human bladder cancer cells. Also our findings suggest that through the inhibition of HSP90 activity, antitumor effect of PI3K/mTOR inhibitor and platinum combination therapy can be synergistically potentiated. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1318-e1319 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Cheol Yong Yoon More articles by this author Mi Kyung Gong More articles by this author Dong Heok Kang More articles by this author Myung Soo Kim More articles by this author Won Sik Jung More articles by this author Young Sik Kim More articles by this author In Rae Cho More articles by this author Young Deuk Choi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
Год издания: 2017
Авторы: Cheol Yong Yoon, Mi Kyung Gong, Dong Heok Kang, Myoung Soo Kim, Won Sik Jung, Young Sik Kim, In Rae Cho, Young Deuk Choi
Издательство: Lippincott Williams & Wilkins
Источник: The Journal of Urology
Ключевые слова: Glutathione Transferases and Polymorphisms
Открытый доступ: bronze
Том: 197
Выпуск: 4S