title: CDDO-Me protects against space radiation-induced transformation of human colon epithelial cells.
abstract: Radiation-induced carcinogenesis is a major concern both for astronauts on long-term space missions and for cancer patients being treated with therapeutic radiation. Exposure to radiation induces oxidative stress and chronic inflammation, which are critical initiators and promoters of carcinogenesis. Many studies have demonstrated that non-steroidal anti-inflammatory drugs and antioxidants can reduce the risk of radiation-induced cancer. In this study, we found that a synthetic triterpenoid, CDDO-Me (bardoxolone methyl), was able to protect human colon epithelial cells (HCECs) against radiation-induced transformation. HCECs that were immortalized by ectopic expression of hTERT and cdk4 and exhibit trisomy for chromosome 7 (a non-random chromosome change that occurs in 37% of premalignant colon adenomas) can be transformed experimentally with one combined exposure to 2 Gy of protons at 1 GeV/nucleon followed 24 h later by 50 cGy of (56)Fe ions at 1 GeV/nucleon. Transformed cells showed an increase in proliferation rate and in both anchorage-dependent and independent colony formation ability. A spectrum of chromosome aberrations was observed in transformed cells, with 40% showing loss of 17p (e.g. loss of one copy of p53). Pretreatment of cells with pharmacological doses of CDDO-Me, which has been shown to induce antioxidative as well as anti-inflammatory responses, prevented the heavy-ion-induced increase in proliferation rate and anchorage-dependent and independent colony formation efficiencies. Taken together, these results demonstrate that experimentally immortalized human colon epithelial cells with a non-random chromosome 7 trisomy are valuable premalignant cellular reagents that can be used to study radiation-induced colorectal carcinogenesis. The utility of premalignant HCECs to test novel compounds such as CDDO-Me that can be used to protect against radiation-induced neoplastic transformation is also demonstrated.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, USA.
authors.forename: Ugur
authors.initials: U
authors.lastname: Eskiocak
authors.forename: Sang Bum
authors.initials: SB
authors.lastname: Kim
authors.forename: Andres I
authors.initials: AI
authors.lastname: Roig
authors.forename: Erin
authors.initials: E
authors.lastname: Kitten
authors.forename: Kimberly
authors.initials: K
authors.lastname: Batten
authors.forename: Crystal
authors.initials: C
authors.lastname: Cornelius
authors.forename: Ying S
authors.initials: YS
authors.lastname: Zou
authors.forename: Woodring E
authors.initials: WE
authors.lastname: Wright
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D003359:Cosmic Radiation; D017931:DNA Primers; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007621:Karyotyping; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid; C445068:bardoxolone methyl