Yonsei Med J.  2020 Jul;61(7):587-596. 10.3349/ymj.2020.61.7.587.

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

  • 1Department of Urology, Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon, Korea
  • 2Department of Medicine, Graduate School of Yonsei University College of Medicine, Seoul, Korea
  • 3School of Dentistry, Pusan National University, Yangsan, Korea
  • 4Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Korea
  • 5Department of Pharmacology, College of Medicine, Konyang University, Daejeon, Korea
  • 6Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, Korea
  • 7Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
  • 8Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea


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.
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.
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.


Bladder cancer; Cisplatin; NVP-BEZ235; 17-DMAG
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