Handrick René, Ganswindt Ute, Faltin Heidrun, Goecke Barbara, Daniel Peter T, Budach Wilfried, Belka Claus, Jendrossek Verena
Department of Radiation Oncology, University of Tübingen, Germany.
Radiother Oncol. 2009 Mar;90(3):413-21. doi: 10.1016/j.radonc.2008.10.021. Epub 2008 Nov 27.
The cyclooxygenase-2-inhibitor celecoxib has been shown to inhibit cell growth and to reduce prostatic intraepithelial neoplasia in mice. The drug was suggested to increase efficacy of ionizing radiation. However, extent and mechanisms of the suggested benefit of celecoxib on the radiation response are still unclear. The aim of the present study was to analyze cytotoxic efficacy of celecoxib in combination with irradiation on human prostate cancer cell lines and to define the importance of pro-apoptotic Bax in this process.
Induction of apoptosis and global and clonogenic cell survival upon irradation- (2-10Gy), celecoxib- (10-75microM) or combined treatment were evaluated in prostate cancer cells by fluorescence microscopy, WST-1 assay and standard colony formation assays.
Celecoxib <25microM caused morphological changes and growth inhibition without substantial apoptosis or radiosensitization in terms of decreased clonogenic cell survival. In contrast, celecoxib 25microM increased radiation-induced cell death and clonogenic kill. While radiation-induced clonogenic death was increased in the presence of Bax, effects of celecoxib or combined treatment were Bax independent.
Our findings reveal Bax-independent beneficial effects of celecoxib on radiation-induced apoptosis and eradication of clonogenic prostate cancer cells in vitro providing a rationale for clinical evaluation of high-dose celecoxib in combination with irradiation in prostate cancer patients.
环氧化酶-2抑制剂塞来昔布已被证明可抑制小鼠细胞生长并减少前列腺上皮内瘤变。该药物被认为可提高电离辐射的疗效。然而，塞来昔布对辐射反应的潜在益处的程度和机制仍不清楚。本研究的目的是分析塞来昔布与辐射联合对人前列腺癌细胞系的细胞毒性作用，并确定促凋亡蛋白Bax在此过程中的重要性。
通过荧光显微镜、WST-1检测和标准集落形成试验，评估辐射（2-10Gy）、塞来昔布（10-75μM）或联合处理对前列腺癌细胞凋亡诱导及总体和克隆形成细胞存活的影响。
浓度低于25μM的塞来昔布可引起形态学改变和生长抑制，但未导致明显凋亡或放射增敏作用（即克隆形成细胞存活率降低）。相反，25μM的塞来昔布可增加辐射诱导的细胞死亡和克隆杀伤。虽然在存在Bax的情况下辐射诱导的克隆性死亡增加，但塞来昔布或联合处理的效果与Bax无关。
我们的研究结果揭示了塞来昔布对辐射诱导的凋亡和体外克隆性前列腺癌细胞根除具有不依赖Bax的有益作用，为在前列腺癌患者中联合使用高剂量塞来昔布与辐射进行临床评估提供了理论依据。
