CDDO-Me Protects Normal Lung and Breast Epithelial Cells but Not Cancer Cells from Radiation

Although radiation therapy is commonly used for treatment for many human diseases including cancer, ionizing radiation produces reactive oxygen species that can damage both cancer and healthy cells. Synthetic triterpenoids, including CDDO-Me, act as anti-inflammatory and antioxidant modulators primarily by inducing the transcription factor Nrf2 to activate downstream genes containing antioxidant response elements (AREs). In the present series of experiments, we determined if CDDO-Me can be used as a radioprotector in normal non-cancerous human lung and breast epithelial cells, in comparison to lung and breast cancer cell lines. A panel of normal non-cancerous, partially cancer progressed, and cancer cell lines from both lung and breast tissue was exposed to gamma radiation with and without pre-treatment with CDDO-Me. CDDO-Me was an effective radioprotector when given ∼18 hours before radiation in epithelial cells (average dose modifying factor (DMF) = 1.3), and Nrf2 function was necessary for CDDO-Me to exert these radioprotective effects. CDDO-Me did not protect cancer lines tested from radiation-induced cytotoxicity, nor did it protect experimentally transformed human bronchial epithelial cells (HBECs) with progressive oncogenic manipulations. CDDO-Me also protected human lymphocytes against radiation-induced DNA damage. A therapeutic window exists in which CDDO-Me protects normal cells from radiation by activating the Nrf2 pathway, but does not protect experimentally transformed or cancer cell lines. This suggests that use of this oral available, non-toxic class of drug can protect non-cancerous healthy cells during radiotherapy, resulting in better outcomes and less toxicity for patients.尽管放射疗法是包括癌症在内的多种人类疾病的常用治疗手段，但电离辐射会产生活性氧物种（reactive oxygen species），既可损伤癌细胞，也可损伤健康细胞。合成三萜类化合物（包括CDDO-Me）主要通过诱导转录因子（transcription factor）核因子E2相关因子2（Nuclear factor erythroid 2-related factor 2, Nrf2）激活携带抗氧化反应元件（antioxidant response elements, AREs）的下游基因，从而发挥抗炎与抗氧化调节作用。在本系列实验中，我们探究了CDDO-Me能否作为辐射防护剂（radioprotector）应用于正常非癌变的人类肺、乳腺上皮细胞，并以肺、乳腺癌细胞系作为对照。我们将一组源自肺与乳腺组织的正常非癌变、部分癌变进展期以及癌细胞系分别暴露于γ射线（gamma radiation）照射，同时设置预先经CDDO-Me处理与未处理的对照分组。在上皮细胞中，若在辐射前约18小时给予CDDO-Me，该化合物可发挥有效的辐射防护作用（平均剂量修正因子（dose modifying factor, DMF）=1.3），且Nrf2的功能是CDDO-Me实现此类辐射保护效应的必要条件。CDDO-Me无法保护受试癌细胞系免受辐射诱导的细胞毒性损伤，同样也无法保护经过渐进式致癌操作的实验转化人类支气管上皮细胞（Human Bronchial Epithelial Cells, HBECs）。此外，CDDO-Me可保护人类淋巴细胞免受辐射诱导的DNA损伤。本研究证实存在一处治疗窗口：CDDO-Me可通过激活Nrf2通路保护正常细胞免受辐射损伤，但无法保护实验转化细胞或癌细胞系。这表明，这类口服可用、无毒的药物可在放射治疗过程中保护正常非癌变的健康细胞，从而改善患者的治疗结局并降低毒副作用。