The clinically used PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in a murine model of third‐degree burn injury

Abstract

BACKGROUND AND PURPOSEThe PARP inhibitor olaparib has recently been approved for human use for the therapy of cancer. Considering the role of PARP in critical illness, we tested the effect of olaparib in a murine model of burn injury, in order to begin exploring the feasibility of repurposing olaparib for the therapy of burn patients. EXPERIMENTAL APPROACHMice were subjected to scald burn injury and randomized into vehicle or olaparib (10 mg·kg À1 ·day À1 i.p.) groups. Outcome variables included indices of organ injury, clinical chemistry parameters, plasma levels of inflammatory mediators (at 24 h, 7 and 21 days) and burn wound size (at 21 days). KEY RESULTSOlaparib reduced myeloperoxidase levels in heart and lung homogenates and reduced malondialdehyde levels in all tissues 24 h post-burn. Olaparib also reduced circulating alkaline aminotransferase, amylase and blood urea nitrogen and creatinine levels, indicative of protection against hepatic, pancreatic and renal dysfunction. Pro-inflammatory mediator (TNF-α, IL-1β, IFN-γ, GCSF, GM-CSF, eotaxin, KC, MIP-1-α and IL-3, 6 and 12) levels as well as the levels of several mediators that are generally considered anti-inflammatory (IL-4, 10 and 13) were reduced by olaparib. Plasma troponin-I levels (an indicator of skeletal muscle damage) was also attenuated by olaparib. Finally, olaparib stimulated wound healing. CONCLUSIONS AND IMPLICATIONSThe clinically approved PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in murine burn injury. The data raise the potential utility of olaparib for severe burn injury.

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

“…Although the clear focus with olaparib -both preclinically and clinically -has been the therapy of various cancers, several groups have started conducting preclinical studies with olaparib in the context of various non-oncological applications, with an eye on future therapeutic repurposing. These efforts, so far, have demonstrated (1) protective effects of olaparib in vitro against NMDA receptor stimulation induced or oxygen-glucose deprivation induced death in differentiated human neurons (Xu et al, 2016) and in retinal pigment epithelial cell lines exposed to H 2 O 2 (Jang et al, 2017) and in cisplatin-induced injury in chronic myeloid leukaemia cells (Xiao and Kan, 2017), (2) protective effects of olaparib in a mouse model of transient middle cerebral artery occlusion and reperfusion (Teng et al, 2016), (3) protective effects of olaparib in various models of model of lung injury/lung inflammation, either induced by endotoxin (Kapoor et al, 2015) or in asthma models elicited by senzitization to ovalbumin (Ghonim et al, 2015a) or to house dust mites (Ghonim et al, 2015b), (4) protective effects of olaparib in various models of multiple organ dysfunction, either elicited by bacterial lipopolysaccharide (Kapoor et al, 2015) or by third-degree thermal injury (Ahmad et al, 2018), and (5) protective effects of olaparib in rodent models of acute and chronic liver failure Mukhopadhyay et al, 2017). The current data confirm and extend these findings and demonstrate the protective effect of olaparib in oxidant-challenged cardiac myocytes and in transplanted rat hearts.…”

Poly(ADP-Ribose) Polymerase Inhibition in Acute Lung Injury. A Reemerging Concept

“…Multiple lines of in vivo experiments have demonstrated that pharmacological PARP inhibitors or PARP1 deficiency can significantly improve the outcomes of various animal models of acute and chronic lung injury, including endotoxin- or sepsis-induced lung injury, pancreatitis-induced lung injury, lung inflammation elicited by various agents (e.g., zymosan, carrageenan or elastase), ventilator-induced lung injury, environmental agent– or drug-induced lung injury, or lung fibrosis and allergy/asthma–associated lung inflammation and dysfunction ( 26 – 84 ). Table 1 focuses on the findings related to the effect of PARP inhibitors in various forms of ALI and lung inflammation.…”

An Open Label, Pilot Study of Veliparib and Lapatinib in Patients with Metastatic, Triple Negative Breast Cancer

“…Anti-inflammatory effects of veliparib have been described in traumatic brain injuries in animal models when utilized up to 24 hours after the event [23]. Furthermore, PARP inhibitors have demonstrated effects on reducing pro-inflammatory mediators in the plasma such as TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-12, IP-10, KC on in vitro models of pancreatitis as well as in vivo models of wound healing injuries [24,25]. Of note, veliparib is the only PARP inhibitor that has been successfully combined with other therapies including chemotherapy without significant dose reductions.…”