Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions
Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions
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DOI：
10.1016/j.radonc.2012.11.014
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发表时间：
2013-01-01
影响因子：
5.7
通讯作者：
Supiot, Stephane
中科院分区：
文献类型：
--
作者：
Potiron, Vincent A.;Abderrhamani, Rym;Supiot, Stephane
背景和目的：尽管进行了适当的放射治疗，但高危前列腺癌患者通常会出现局部复发和进展为转移性疾病。放射抗性可能是由于肿瘤缺氧，但也由于70%的前列腺癌中存在的PTEN突变/缺失。我们研究了新型PI 3 K/mTOR抑制剂BEZ 235是否可以使前列腺癌细胞对辐射敏感并降低缺氧诱导的辐射抗性。使用两种前列腺癌细胞系PC 3（PTEN-/-）和DU 145（PTEN+/+）在体外和体内研究BEZ 235的潜在放射增敏性质，结果：BEZ 235以剂量依赖性方式迅速抑制PI 3 K和mTOR信号转导，并抑制两种细胞系的增殖和克隆形成存活，与PTEN状态无关。在体内，BEZ 235预处理增强了放射疗法对小鼠中的PC 3异种移植肿瘤的功效，而不诱导肠道放射毒性。在培养中，BEZ 235以相当的方式放射致敏两种细胞系。此外，BEZ 235抑制PI 3 K/mTOR活化，并在常氧和缺氧下对两种细胞系进行放射增敏。BEZ 235的放射增敏作用与γ-H2 AX灶修复减少和G2/M期细胞阻滞增加相关。结论：BEZ 235对常氧和缺氧前列腺癌细胞均具有较强的放射增敏作用。(c)2013爱思唯尔爱尔兰有限公司版权所有。放射治疗和肿瘤学106（2013）138-146
Background and purpose: Despite appropriate radiotherapy, high-risk prostate cancer patients often experience local relapse and progression to metastatic disease. Radioresistance may be due to tumor-hypoxia but also due to the PTEN mutation/deletion present in 70% prostate cancers. We investigated whether the novel PI3K/mTOR inhibitor BEZ235 might sensitize prostate cancer cells to radiation and reduce hypoxia-induced radioresistance.Materials and methods: The potential radiosensitizing properties of BEZ235 were investigated in vitro and in vivo using two prostate cancer cell lines, PC3 (PTEN-/-) and DU145 (PTEN+/+), under normoxic (21% O-2) and hypoxic (0.5% O-2) conditions.Results: BEZ235 rapidly inhibited PI3K and mTOR signaling in a dose dependent manner and limited tumor cell proliferation and clonogenic survival in both cell lines independently of PTEN status. In vivo, BEZ235 pretreatment enhanced the efficacy of radiation therapy on PC3 xenograft tumors in mice without inducing intestinal radiotoxicity. In culture, BEZ235 radiosensitized both cell lines in a comparable manner. Moreover, BEZ235 inhibited PI3K/mTOR activation and radiosensitized both cell lines under normoxia and hypoxia. BEZ235 radiosensitizing effects correlated with a decrease in gamma H2AX foci repair and increased G2/M cell cycle arrest.Conclusions: BEZ235 is a potent radiosensitizer of normoxic and hypoxic prostate cancer cells. (c) 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 106 (2013) 138-146