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Synergistic Antitumor Effects of Combined Treatment with HSP90 Inhibitor and PI3K/mTOR Dual Inhibitor in Cisplatin-Resistant Human Bladder Cancer Cells

 Hyung Joon Kim  ;  Mi Kyung Gong  ;  Cheol Yong Yoon  ;  Jaeku Kang  ;  Mijin Yun  ;  Nam Hoon Cho  ;  Sun Young Rha  ;  Young Deuk Choi 
 YONSEI MEDICAL JOURNAL, Vol.61(7) : 587-596, 2020-07 
Journal Title
Issue Date
Antineoplastic Agents / therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols ; Apoptosis / drug effects ; Benzoquinones / pharmacology ; Benzoquinones / therapeutic use* ; Cell Cycle Checkpoints / drug effects ; Cell Line, Tumor ; Cisplatin / pharmacology ; Cisplatin / therapeutic use* ; DNA Damage / drug effects ; Drug Resistance, Neoplasm* ; Humans ; Imidazoles ; Lactams, Macrocyclic / pharmacology ; Lactams, Macrocyclic / therapeutic use* ; Phosphatidylinositol 3-Kinases / metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors / pharmacology ; Protein Kinase Inhibitors / therapeutic use* ; Quinolines ; TOR Serine-Threonine Kinases / antagonists & inhibitors* ; TOR Serine-Threonine Kinases / metabolism ; Urinary Bladder Neoplasms / drug therapy*
17-DMAG ; Bladder cancer ; Cisplatin ; NVP-BEZ235
Purpose: The current study aimed to investigate the synergistic antitumor effect of combined treatment with 17-DMAG (HSP90 inhibitor) and NVP-BEZ235 (PI3K/mTOR dual inhibitor) on cisplatin-resistant human bladder cancer cells.

Materials and methods: Human bladder cancer cells exhibiting cisplatin resistance (T24R2) were exposed to escalating doses of 17-DMAG (2.5-20 nM) with or without NVP-BEZ236 (0.5-4 μM) in combination with cisplatin. Antitumor effects were assessed by CCK-8 analysis. Based on the dose-response study, synergistic interactions between the two regimens were evaluated using clonogenic assay and combination index values. Flow cytometry and Western blot were conducted to analyze mechanisms of synergism.

Results: Dose- and time-dependent antitumor effects for 17-DMAG were observed in both cisplatin-sensitive (T24) and cisplatin-resistant cells (T24R2). The antitumor effect of NVP-BEZ235, however, was found to be self-limiting. The combination of 17-DMAG and NVP-BEZ235 in a 1:200 fixed ratio showed a significant antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range, and clonogenic assay showed compatible results with synergy tests. Three-dimensional analysis revealed strong synergy between the two drugs with a synergy volume of 201.84 μM/mL²%. The combination therapy resulted in G1-phase cell cycle arrest and caspase-dependent apoptosis confirmed by the Western blot.

Conclusion: HSP90 inhibitor monotherapy and in combination with the PI3K/mTOR survival pathway inhibitor NVP-BEZ235 shows a synergistic antitumor effect in cisplatin-resistant bladder cancers, eliciting cell cycle arrest at the G1 phase and induction of caspase-dependent apoptotic pathway.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Urology (비뇨의학교실) > 1. Journal Papers
Yonsei Authors
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Yun, Mi Jin(윤미진) ORCID logo https://orcid.org/0000-0002-1712-163X
Yoon, Cheol Yong(윤철용)
Cho, Nam Hoon(조남훈) ORCID logo https://orcid.org/0000-0002-0045-6441
Choi, Young Deuk(최영득) ORCID logo https://orcid.org/0000-0002-8545-5797
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