Nuclear Countermeasure Activity of TP508 Linked to Restoration of Endothelial Function and Acceleration of DNA Repair

Abstract

There is increasing evidence that radiation-induced damage to endothelial cells and loss of endothelial function may contribute to both acute radiation syndromes and long-term effects of whole-body nuclear irradiation. Therefore, several drugs are being developed to mitigate the effects of nuclear radiation, most of these drugs will target and protect or regenerate leukocytes and platelets. Our laboratory has demonstrated that TP508, a 23-amino acid thrombin peptide, activates endothelial cells and stem cells to revascularize and regenerate tissues. We now show that TP508 can mitigate radiation-induced damage to endothelial cells in vitro and in vivo. Our in vitro results demonstrate that human endothelial cells irradiation attenuates nitric oxide (NO) signaling, disrupts tube formation and induces DNA double-strand breaks (DSB). TP508 treatment reverses radiation effects on NO signaling, restores tube formation and accelerates the repair of radiation-induced DSB. The radiation-mitigating effects of TP508 on endothelial cells were also seen in CD-1 mice where systemic injection of TP508 stimulated endothelial cell sprouting from aortic explants after 8 Gy irradiation. Systemic doses of TP508 that mitigated radiation-induced endothelial cell damage, also significantly increased survival of CD-1 mice when injected 24 h after 8.5 Gy exposure. These data suggest that increased survival observed with TP508 treatment may be due to its effects on vascular and microvascular endothelial cells. Our study supports the usage of a regenerative drug such as TP508 to activate endothelial cells as a countermeasure for mitigating the effects of nuclear radiation.

The importance of the vascular endothelial barrier in the immune-inflammatory response induced by radiotherapy

“…166 However, the authors felt that targeting specific thrombin functions may be superior to global thrombin inhibition. On the other hand, the administration of the thrombin peptide TP508 has been shown to activate endothelial cells and stem cells to revascularise and regenerate tissues in a whole-body irradiation model, 167,168 suggesting a possible use to limit RT side-effects.…”

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part III. Countermeasures under early stages of development along with ‘standard of care’ medicinal and procedures not requiring regulatory approval for use

“…The suggestion has been made that TP508 mitigates GI injury by activating radioresistant stem cells and increasing the stemness of intestinal crypts to restore and maintain GI integrity. One recent study confirmed the radiomitigative potential of TP508 when administered to CD-1 outbred mice 24 h after 8.5 Gy (0.458 Gy/min) 137 Cs c-irradiation (Olszewska-Pazdrak et al 2016). This study, along with other data, suggests that increased survival following TP508 treatments may be due in part to the agent's effect on vascular endothelial cells.…”

High replication stress and limited Rad51-mediated DNA repair capacity, but not oxidative stress, underlie oligodendrocyte precursor cell radiosensitivity

“…To establish a robust model amenable to systematic analysis, we first isolated mouse embryonic NSPCs (E12.5) and OPCs (E17) from wildtype, outbred CD-1 mice that are an established model for brain and radiation research ( 38 , 48 , 49 ), and differentiated these ex vivo into the main neural cell types ( 27 ) outlined in Figure 1A . In this system, the cultures antigenically and morphologically recapitulated their in vivo counterparts when examined by immunofluorescence (for further rationale for using this model system, please see Supplemental Information).…”