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

被引：14

作者：

Kim, Hyung Joon ^{[1
,2
]}

Gong, Mi Kyung ^{[3
,4
]}

Yoon, Cheol Yong ^{[4
]}

Kang, Jaeku ^{[5
]}

Yun, Mijin ^{[2
,6
]}

Cho, Nam Hoon ^{[2
,7
]}

Rha, Sun Young ^{[2
,8
]}

Choi, Young Deuk ^{[2
,4
]}

机构：

[1] Konyang Univ, Myunggok Med Res Inst, Dept Urol, Coll Med, Daejeon, South Korea

[2] Yonsei Univ, Dept Med, Grad Sch, Coll Med, Seoul, South Korea

[3] Pusan Natl Univ, Sch Dent, Yangsan, South Korea

[4] Yonsei Univ, Urol Sci Inst, Dept Urol, Coll Med, 50-1 Yonsei Ro, Seoul 03722, South Korea

[5] Konyang Univ, Coll Med, Dept Pharmacol, Daejeon, South Korea

[6] Yonsei Univ, Dept Nucl Med, Coll Med, Seoul, South Korea

[7] Yonsei Univ, Dept Pathol, Coll Med, Seoul, South Korea

[8] Yonsei Univ, Dept Internal Med, Div Med Oncol, Coll Med, Seoul, South Korea

来源：

YONSEI MEDICAL JOURNAL | 2020年 / 61卷 / 07期

基金：

新加坡国家研究基金会;

关键词：

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

D O I：

10.3349/ymj.2020.61.7.587

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Purpose: The current study aimed to investigate the synergistic antitumor effect of combined treatment with 17-DMAG (IISP90 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 mu M) 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 mu M/mL(2)%. 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.

引用

页码：587 / 596

页数：10

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