title: DIM (3,3'-diindolylmethane) confers protection against ionizing radiation by a unique mechanism.
abstract: DIM (3,3'-diindolylmethane), a small molecule compound, is a proposed cancer preventive agent that can be safely administered to humans in repeated doses. We report that administration of DIM in a multidose schedule protected rodents against lethal doses of total body irradiation up to 13 Gy, whether DIM dosing was initiated before or up to 24 h after radiation. Physiologic submicromolar concentrations of DIM protected cultured cells against radiation by a unique mechanism: DIM caused rapid activation of ataxia-telangiectasia mutated (ATM), a nuclear kinase that regulates responses to DNA damage (DDR) and oxidative stress. Subsequently, multiple ATM substrates were phosphorylated, suggesting that DIM induces an ATM-dependent DDR-like response, and DIM enhanced radiation-induced ATM signaling and NF-κB activation. DIM also caused activation of ATM in rodent tissues. Activation of ATM by DIM may be due, in part, to inhibition of protein phosphatase 2A, an upstream regulator of ATM. In contrast, DIM did not protect human breast cancer xenograft tumors against radiation under the conditions tested. In tumors, ATM was constitutively phosphorylated and was not further stimulated by radiation and/or DIM. Our findings suggest that DIM is a potent radioprotector and mitigator that functions by stimulating an ATM-driven DDR-like response and NF-κB survival signaling.
authors.affiliation: Departments of Oncology, Radiation Medicine, and Biochemistry and Molecular and Cell Biology, Georgetown University Medical Center, Washington, DC 20057.
authors.forename: Saijun
authors.initials: S
authors.lastname: Fan
authors.forename: Qinghui
authors.initials: Q
authors.lastname: Meng
authors.forename: Jiaying
authors.initials: J
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiao
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: Anatoly
authors.initials: A
authors.lastname: Dritschilo
authors.forename: Eliot M
authors.initials: EM
authors.lastname: Rosen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D020552:Comet Assay; D004789:Enzyme Activation / Q000187:drug effects*; D005260:Female; D049452:Green Fluorescent Proteins; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008156:Luciferases; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011833:Radiation Injuries, Experimental / Q000188:drug therapy / Q000517:prevention & control*; D011839:Radiation, Ionizing; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007211:Indoles; D034741:RNA, Small Interfering; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D008156:Luciferases; D064007:Ataxia Telangiectasia Mutated Proteins; D054648:Protein Phosphatase 2; C016392:3,3'-diindolylmethane