Abstract
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.
Highlights
Radiation therapy is a common treatment for cancer patients, ionizing radiation (IR) produces reactive oxygen species (ROS) and is known to damage cellular components in healthy cells, leading to damaged bases and DNA breaks, resulting in chromosomal aberrations, mutagenesis, carcinogenesis, and cell death [1, 2]
To confirm that CDDO-Me (Fig. 1B) activates the Nrf2 pathway in the cells used, human bronchial epithelial cells (HBECs) 3KT (Lung-3) and HME1 (Breast-1) transfected with the antioxidant response elements (AREs)-luciferase reporter were treated with CDDO-Me or DMSO
Protein lysates collected at various times after CDDO-Me 10 nM treatment of normal Lung-3 cells showed an increase of Nrf2/ARE downstream targets, including heme oxygenase (HO1), NADPH dehydrogenase quinone (NQO1), and peroxiredoxin (PRX1) (Fig. 1E; S1 Fig.)
Summary
Radiation therapy is a common treatment for cancer patients, ionizing radiation (IR) produces reactive oxygen species (ROS) and is known to damage cellular components in healthy cells, leading to damaged bases and DNA breaks, resulting in chromosomal aberrations, mutagenesis, carcinogenesis, and cell death [1, 2]. Are these effects responsible for causing radiation sickness and other toxic side effects in cancer patients treated with ionizing or proton radiation therapy, they are a important consideration for first responders to nuclear accidents, astronauts on long-term space missions, or any other situation where individuals are exposed to radiation. In order for these agents to be realistically efficacious, they cannot provide the same level of protection to cancerous cells
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