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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

Yonsei Medical Journal 2020년 61권 7호 p.587 ~ 596
김형준, 공미경, 윤철용, 강재구, 윤미진, 조남훈, 라선영, 최영득,
소속 상세정보
김형준 ( Kim Hyung-Joon ) - Konyang University College of Medicine Department of Urology
공미경 ( Gong Mi-Kyung ) - Pusan National University School of Dentistry
윤철용 ( Yoon Cheol-Yong ) - Yonsei University College of Medicine Department of Urology
강재구 ( Kang Jae-Ku ) - Konyang University College of Medicine Department of Pharmacology
윤미진 ( Yun Mi-Jin ) - Yonsei University College of Medicine Department of Nuclear Medicine
조남훈 ( Cho Nam-Hoon ) - Yonsei University College of Medicine Department of Pathology
라선영 ( Rha Sun-Young ) - Yonsei University College of Medicine Department of Internal Medicine
최영득 ( Choi Young-Deuk ) - Yonsei University College of Medicine Department of Urology

Abstract


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.

키워드

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

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