Targeting NF-κB to Prevent Radiation-Induced Carcinogenesis

摘要

Ionizing radiation inflicts damage to cells in large part through the generation of chemical intermediates that damage DNA and generate DNA strand breaks. Radiation-induced late normal tissue toxicity is the outcome of changes in tissue following exposure to radiation that precede overt toxicity. These events include mitotic cell death especially in bone marrow and mucosal tissue, and the activation of inflammatory responses that can lead to blood vessel damage, tissue necrosis resulting from lack of oxygen and excessive extracellular matrix deposition (fibrosis). While antioxidants can prevent damage by moderating the chemistry of DNA strand breaks, other agents known as radiation mitigators can be used soon after exposure to protect essential compartments such as the bone marrow from collapse. These include agents that reinforce the rapid development of mature bone marrow and mucosa. Medical management of acute radiation syndrome following accidental exposures to ionizing radiation (IR) involves attempts to reduce the risks of infection and hemorrhage resulting from bone marrow aplasia. This involves stimulating the proliferation and differentiation of residual non-impacted or radio-resistant hematopoietic stem and progenitor cells (HSPC) with hematopoietic growth factors. Soon after irradiation radiosensitive HSPC have been shown to undergo apoptosis. It has therefore been proposed that antiapoptotic cytokines including stem cell factor, Flt-3 ligand, thrombopoietin, and interleukin-3 could be employed acutely to prevent this cell death. Moreover, acute exposure to high doses of IR induces sequential, deleterious effects responsible for a delayed multiple organ dysfunction syndrome. Of course, the caveat of preventing the death of cells with damaged DNA is carcinogenesis resulting from DNA mutations in critical genes. NF-κB constitutes a family of transcription factors best associated with mediating the inflammatory response. In cancer cells the activation of the inhibitor of-κB kinase (IKK) and consequently the NF-κB pathway increases resistance to ionizing radiation (IR) by facilitating cell survival, despite the presence of DNA damage and mutations. A number of small molecule inhibitors of NF-κB have been described. I discuss the potential benefit of targeting NF-κB for the prevention of radiation-induced cancers.