Alpha-2-macroglobulin as a radioprotective agent: a review

Abstract

Radiation is an important modality in cancer treatment, and eighty percent of cancer patients need radiotherapy at some point during their clinical management. However, radiation-induced damage to normal tissues restricts the therapeutic doses of radiation that can be delivered to tumours and thereby limits the effectiveness of the treatment. The use of radioprotectors represents an obvious strategy to obtain better tumour control using a higher dose in radiotherapy. However, most of the synthetic radioprotective compounds studied have shown inadequate clinical efficacy owing to their inherent toxicity and high cost. Hence, the development of radioprotective agents with lower toxicity and an extended window of protection has attracted a great deal of attention, and the identification of alternative agents that are less toxic and highly effective is an absolute necessity. Recent studies have shown that alpha-2-macroglobulin (α2M) possesses radioprotective effects. α2M is a tetrameric, disulfide-rich plasma glycoprotein that functions as a non-selective inhibitor of different types of non-specific proteases and as a carrier of cytokines, growth factors, and hormones. α2M induces protein factors whose interplay underlies radioprotection, which supports the idea that α2M is the central effector of natural radioprotection in the rat. Pretreatment with α2M has also induced a significant reduction of irradiation-induced DNA damage and the complete restoration of liver and body weight. Mihailović et al. concluded that the radioprotection provided by α2M was in part mediated through cytoprotection of new blood cells produced in the bone marrow; these authors also indicated that an important aspect of the radioprotective effect of amifostine was the result of the induction of the endogenous cytoprotective capability of α2M. The radioprotective effects of α2M are possibly due to antioxidant, anti-fibrosis, and anti-inflammatory functions, as well as the maintenance of homeostasis, and enhancement of the DNA repair and cell recovery processes. This review is the first to summarise the observations and elucidate the possible mechanisms responsible for the beneficial effects of α2M. The lacunae in the existing knowledge and directions for future research are also addressed.

Keywords: Alpha-2-macroglobulin (α2M); ionising radiation; mechanism; radiation-induced fibrosis; radioprotection.

Figure 1

Radiation-induced fibrosis theory.

Figure 2

The potential mechanism of antioxidant effect of α₂M on radiation injury.

Figure 3

The binding of α₂M with pro-inflammatory cytokines.

Figure 4

Potential mechanisms responsible for radioprotection of α₂M. [1], α₂M binds LRP-1 on the fibroblast membrane to activate NFκB and promote the nuclear translocation and binding of NFκB to target genes (MnSOD genes), resulting in the increased expression of MnSOD. MnSOD then scavenges ROS (O₂^–) by catalysing its conversion to hydrogen peroxide and oxygen; [2], α₂M functions as an inflammatory fluid proteinase scavenger and maintains homeostasis; [3], α₂M provides natural radioresistance and avoid radiation injury; [4], α₂M binds cytokines and growth factors and inhibits the processes of fibrosis and inflammation; [5], α₂M binds cytokines to develop α₂M-cytokines complex. The α₂M-cytokines complex plays essential roles in the regulation of cellular functions that bring about tissue repair and remodelling. Moreover, α₂M plays a role in repair and remodelling by promoting hematopoietic system cells production.