Department of Urology, Nara Medical University, Nara, Japan.
BMC Urol. 2013 Jan 5;13:1. doi: 10.1186/1471-2490-13-1.
COX-2 inhibitors have an antitumor potential and have been verified by many researchers. Treatment of cancer cells with external stressors such as irradiation can stimulate the over-expression of COX-2 and possibly confer radiation resistance. In this study, we tested if topical diclofenac, which inhibits both COX-1 and COX-2, administration rendered prostate tumor cells sensitize to the effects of radiation.
LNCaP-COX-2 and LNCaP-Neo cells were treated with 0 to 1000 μM diclofenac. Next, a clonogenic assay was performed in which cells were subjected to irradiation (0 to 4 Gy) with or without diclofenac. COX-2 expression and other relevant molecules were measured by real-time PCR and immunohistochemistry after irradiation and diclofenac treatment. In addition, we assessed the tumor volumes of xenograft LNCaP-COX-2 cells treated with topical diclofenac with or without radiation therapy (RT).
LNCaP-COX-2 and LNCaP-Neo cell lines experienced cytotoxic effects of diclofenac in a dose related manner. Clonogenic assays demonstrated that LNCaP-COX-2 cells were significantly more resistant to RT than LNCaP-Neo cells. Furthermore, the addition of diclofenac sensitized LNCaP-COX-2 not but LNCaP-Neo cells to the cytocidal effects of radiation. In LNCaP-COX-2 cells, diclofenac enhanced radiation-induced apoptosis compared with RT alone. This phenomenon might be attributed to enhancement of RT-induced TRAIL expression as demonstrated by real-time PCR analysis. Lastly, tumor volumes of LNCaP-COX-2 cells xenograft treated with diclofenac or RT alone was >4-fold higher than in mice treated with combined diclofenac and radiation (p<0.05).
These in vitro and in vivo findings suggest that conventional COX inhibitor, diclofenac enhances the effect of RT on prostate cancer cells that express COX-2. Thus, diclofenac may have potential as radiosensitizer for treatment of prostate cancer.
环氧化酶-2（COX-2）抑制剂具有抗肿瘤作用，这已被许多研究人员证实。用外部应激源（如辐射）处理癌细胞可以刺激 COX-2 的过度表达，并可能赋予辐射抗性。在这项研究中，我们测试了局部用双氯芬酸（可同时抑制 COX-1 和 COX-2）是否可使前列腺肿瘤细胞对辐射的作用敏感。
用 0 至 1000μM 双氯芬酸处理 LNCaP-COX-2 和 LNCaP-Neo 细胞。接下来，进行集落形成测定，其中用或不用双氯芬酸对细胞进行照射（0 至 4Gy）。照射和双氯芬酸处理后，通过实时 PCR 和免疫组织化学测定 COX-2 表达和其他相关分子。此外，我们评估了用或不用放射治疗（RT）的局部用双氯芬酸治疗的异种移植 LNCaP-COX-2 细胞的肿瘤体积。
LNCaP-COX-2 和 LNCaP-Neo 细胞系以剂量相关的方式经历了双氯芬酸的细胞毒性作用。集落形成测定表明，LNCaP-COX-2 细胞对 RT 的抵抗力明显强于 LNCaP-Neo 细胞。此外，添加双氯芬酸使 LNCaP-COX-2 而非 LNCaP-Neo 细胞对辐射的细胞杀伤作用敏感。在 LNCaP-COX-2 细胞中，与单独 RT 相比，双氯芬酸增强了辐射诱导的细胞凋亡。通过实时 PCR 分析表明，这种现象可能归因于 RT 诱导的 TRAIL 表达增强。最后，单独用双氯芬酸或 RT 治疗的 LNCaP-COX-2 细胞异种移植的肿瘤体积比用联合用双氯芬酸和辐射治疗的小鼠高 4 倍以上（p<0.05）。
这些体外和体内研究结果表明，传统的 COX 抑制剂双氯芬酸增强了表达 COX-2 的前列腺癌细胞对 RT 的作用。因此，双氯芬酸可能具有作为治疗前列腺癌的放射增敏剂的潜力。
