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DIM (3,3′-diindolylmethane) confers protection against ionizing radiation by a unique mechanism

Significance DIM (3,3′-diindolylmethane) is a small molecule compound under investigation as a cancer preventive agent. This research addresses a potential usage of DIM as a medical countermeasure to prevent or mitigate acute radiation syndrome due to whole body exposure. In this regard, DIM can be administered safely to humans and animals by oral or subcutaneous routes. DIM may also be useful in preventing or mitigating late normal tissue damage due to partial body radiation exposure during cancer treatment. DIM works, in part, by a mechanism distinct from other radioprotectors and mitigators involving stimulation of the DNA damage response, including DNA repair, and activation of cell survival signaling through the transcription factor NF-κB. 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.