ON01210.Na (Ex-RAD®) Mitigates Radiation Damage through Activation of the AKT Pathway

Abstract

Development of radio-protective agents that are non-toxic is critical in light of ever increasing threats associated with proliferation of nuclear materials, terrorism and occupational risks associated with medical and space exploration. In this communication, we describe the discovery, characterization and mechanism of action of ON01210.Na, which effectively protects mouse and human bone marrow cells from radiation-induced damage both in vitro and in vivo. Our results show that treatment of normal fibroblasts with ON01210.Na before and after exposure to ionizing radiation provides dose dependent protection against radiation-induced damage. Treatment of mice with ON01210.Na prior to radiation exposure was found to result in a more rapid recovery of their hematopoietic system. The mechanistic studies described here show that ON01210.Na manifests its protective effects through the up-regulation of PI3-Kinase/AKT pathways in cells exposed to radiation. These results suggest that ON 01210.Na is a safe and effective radioprotectant and could be a novel agent for use in radiobiological disasters.

Effects of formulation and route of administration on the systemic availability of Ex‐RAD®, a new radioprotectant, in preclinical species

“…ON 01210.Na has also demonstrated good radioprotection in an in vivo mouse model 17–19, 22, 24. Thirty‐day survival studies have been performed in mice treated with the Tween suspension formulation of ON 01210.Na (500 mg/kg, s.c. injection), administered 24 h and 15 min prior to γ‐radiation exposure (7.5 or 8.0 Gy).…”

“…Unlike anti‐oxidants or free radical scavengers, the mechanism of action of ON 01210.Na is unique. ON 01210.Na prevents apoptosis by inhibiting the phosphorylation of p53, protects granulocyte macrophage colony‐forming units (GMCFU) in bone marrow progenitor cells, and regenerates intestinal crypt cells 17, 18. ON 01210.Na has been shown to be non‐toxic and effective in increasing survival rate at the cellular and tissue level in various animal radiation models by enhancing cell survival and DNA repair mechanisms 19–22.…”

PROTECTION OF FEMALE C3H MICE AGAINST WHOLE-BODY gamma-IRRADIATION WITH 2,3-DIMETHYL-6-((2-DIMETHYLAMINO)ETHYL)-6H-INDOLO[2,3-b]QUINOXALINE (B220)

“…5,6,8,11 Ex-Rad™ was reported to manifest its protective effects through up-regulation of PI3-Kinase/AKT pathways in cells exposed to radiation. 19 A suggested protective mechanism for DIM proceeds through activation of the nuclear kinase at axiateleangiectasia mutated (ATM) regulating responses to DNA damage and oxidative stress, and NF-κB activation.…”

Biomarkers for acute radiation syndrome: challenges for developing radiation countermeasures following animal rule

“…For example, based on investigations in the murine, canine, nonhuman primates (NHPs), and human [2], granulocyte colonystimulating factor (G-CSF) and interleukin-6 (IL-6) have been identified as biomarkers for CBLB502/Entolimod. Similarly, pAKT has been suggested as biomarker for the development of Ex-RAD/Recilisib as a radiation countermeasure [3]. There are several other radiation countermeasures under development such as gamma-tocotrienol (GT3), delta-tocotrienol, 5-androstenediol, tocopherol succinate, CBLB612, and CBLB613 that have demonstrated the induction of high levels of G-CSF in mice.…”