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首页> 外文期刊>Cell cycle >Low-dose Hsp90 inhibitors tumor-selectively sensitize bladder cancer cells to chemoradiotherapy.
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Low-dose Hsp90 inhibitors tumor-selectively sensitize bladder cancer cells to chemoradiotherapy.

机译：低剂量Hsp90抑制剂对肿瘤有选择性地使膀胱癌细胞对放化疗敏感。

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Although radical cystectomy with urinary diversion is the standard treatment for muscle-invasive bladder cancer (MIBC), loss of native bladder frequently impairs patient's quality of life (QOL). Bladder-sparing approach incorporating chemoradiotherapy (CRT) improves QOL while not compromising survival outcomes in MIBC patients. In this approach, complete response to induction CRT is a prerequisite for bladder preservation and favorable oncological outcomes. We investigated a strategy to potentiate CRT response of bladder cancer cells by using Hsp90 inhibitors in preclinical models. Hsp90 inhibitors at low concentrations, which did not exert cytocidal effects but inactivated key anti-apoptotic proteins including erbB2, Akt, and NF-kappaB, efficiently sensitized bladder cancer cells (T24, 5637 and UM-UC-3 cells) to in vitro CRT by enhancing apoptosis. Importantly, the sensitizing effects were not observed in primarily cultured normal human urothelial cells. We also showed that CRT induces accumulation of nuclear phospho-Akt, which antagonizes apoptosis, and that Hsp90 inhibitors block the cellular process. Hsp90 inhibition sensitized bladder cancer cells to in vitro CRT more effectively than sole or combined inhibition of erbB2 and Akt. In mice UM-UC-3 tumor xenografts model, Hsp90 inhibitors successfully potentiated anti-tumor activity of CRT. These results encourage clinical trials of Hsp90 inhibitors to overcome CRT resistance in patients with MIBC.
机译：尽管根治性膀胱切除术伴尿路转移是肌肉浸润性膀胱癌（MIBC）的标准治疗方法，但自然膀胱的丢失经常损害患者的生活质量（QOL）。结合放化疗的膀胱保留方法可改善QOL，同时不影响MIBC患者的生存结果。在这种方法中，对诱导CRT的完全反应是膀胱保存和良好的肿瘤学结果的前提。我们研究了在临床前模型中通过使用Hsp90抑制剂增强膀胱癌细胞CRT反应的策略。低浓度的Hsp90抑制剂不产生杀细胞作用，但使关键的抗凋亡蛋白（包括erbB2，Akt和NF-κB）失活，从而使膀胱癌细胞（T24、5637和UM-UC-3细胞）有效地体外CRT致敏通过增强细胞凋亡。重要的是，在最初培养的正常人尿路上皮细胞中未观察到敏化作用。我们还表明，CRT诱导核磷酸Akt的积累，从而拮抗细胞凋亡，并且Hsp90抑制剂阻断了细胞过程。 Hsp90抑制比单独或联合抑制erbB2和Akt更有效地使膀胱癌细胞对体外CRT敏感。在小鼠UM-UC-3肿瘤异种移植模型中，Hsp90抑制剂成功增强了CRT的抗肿瘤活性。这些结果鼓励了Hsp90抑制剂克服MIBC患者CRT耐药性的临床试验。

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