title: CDDO-Me protects normal lung and breast epithelial cells but not cancer cells from radiation.
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.
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.
authors.forename: Mariam
authors.initials: M
authors.lastname: El-Ashmawy
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Oliver
authors.initials: O
authors.lastname: Delgado
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.
authors.forename: Agnelio
authors.initials: A
authors.lastname: Cardentey
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.
authors.forename: Woodring E
authors.initials: WE
authors.lastname: Wright
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center at Dallas, Dallas, Texas, United States of America; Center for Excellence in Genomics Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001940:Breast / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000528:radiation effects*; D005260:Female; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008175:Lung Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D011837:Radiation-Protective Agents; D009828:Oleanolic Acid; C445068:bardoxolone methyl