The PARP inhibitor olaparib exerts beneficial effects in mice subjected to cecal ligature and puncture and in cells subjected to oxidative stress without impairing DNA integrity: A potential opportunity for repurposing a clinically used oncological drug for the experimental therapy of sepsis

Akbar Ahmad, Juliana de Camargo Vieira, Aline Haas de Mello, Thais Martins de Lima, Suely Kubo Ariga, Denise Frediani Barbeiro, Hermes Vieira Barbeiro, Bartosz Szczesny, Gábor Törö, Nadiya Druzhyna, Elisa B. Randi, Michela Marcatti, Tracy Toliver-Kinsky, András Kiss, Lucas Liaudet, Reinaldo Salomao, Francisco Garcia Soriano, Csaba Szabo

Research output: Contribution to journalArticle

Abstract

Poly(ADP-ribose)polymerase (PARP)is involved in the pathogenesis of cell dysfunction, inflammation and organ failure during septic shock. The goal of the current study was to investigate the efficacy and safety of the clinically approved PARP inhibitor olaparib in experimental models of oxidative stress in vitro and in sepsis in vivo. In mice subjected to cecal ligation and puncture (CLP)organ injury markers, circulating and splenic immune cell distributions, circulating mediators, DNA integrity and survival was measured. In U937 cells subjected to oxidative stress, cellular bioenergetics, viability and DNA integrity were measured. Olaparib was used to inhibit PARP. The results show that in adult male mice subjected to CLP, olaparib (1–10 mg/kg i.p.)improved multiorgan dysfunction. Olaparib treatment reduced the degree of bacterial CFUs. Olaparib attenuated the increases in the levels of several circulating mediators in the plasma. In the spleen, the number of CD4+ and CD8+ lymphocytes were reduced in response to CLP; this reduction was inhibited by olaparib treatment. Treg but not Th17 lymphocytes increased in response to CLP; these cell populations were reduced in sepsis when the animals received olaparib. The Th17/Treg ratio was lower in CLP-olaparib group than in the CLP control group. Analysis of miRNA expression identified a multitude of changes in spleen and circulating white blood cell miRNA levels after CLP; olaparib treatment selectively modulated these responses. Olaparib extended the survival rate of mice subjected to CLP. In contrast to males, in female mice olaparib did not have significant protective effects in CLP. In aged mice olaparib exerted beneficial effects that were less pronounced than the effects obtained in young adult males. In in vitro experiments in U937 cells subjected to oxidative stress, olaparib (1–100 μM)inhibited PARP activity, protected against the loss of cell viability, preserved NAD + levels and improved cellular bioenergetics. In none of the in vivo or in vitro experiments did we observe any adverse effects of olaparib on nuclear or mitochondrial DNA integrity. In conclusion, olaparib improves organ function and extends survival in septic shock. Repurposing and eventual clinical introduction of this clinically approved PARP inhibitor may be warranted for the experimental therapy of septic shock.

Original languageEnglish (US)
Article number104263
JournalPharmacological Research
Volume145
DOIs
StatePublished - Jul 1 2019

Fingerprint

Investigational Therapies
Punctures
Ligation
Sepsis
Oxidative Stress
Drug Therapy
DNA
Poly(ADP-ribose) Polymerases
Septic Shock
U937 Cells
olaparib
Poly(ADP-ribose) Polymerase Inhibitors
MicroRNAs
Energy Metabolism
Spleen
Lymphocytes
Mitochondrial DNA
NAD

Keywords

  • Cell death
  • DNA
  • Mitochondria
  • Multiorgan dysfunction
  • Sepsis
  • Shock
  • Th17
  • Treg

ASJC Scopus subject areas

  • Pharmacology

Cite this

The PARP inhibitor olaparib exerts beneficial effects in mice subjected to cecal ligature and puncture and in cells subjected to oxidative stress without impairing DNA integrity : A potential opportunity for repurposing a clinically used oncological drug for the experimental therapy of sepsis. / Ahmad, Akbar; Vieira, Juliana de Camargo; Haas de Mello, Aline; de Lima, Thais Martins; Ariga, Suely Kubo; Barbeiro, Denise Frediani; Barbeiro, Hermes Vieira; Szczesny, Bartosz; Törö, Gábor; Druzhyna, Nadiya; Randi, Elisa B.; Marcatti, Michela; Toliver-Kinsky, Tracy; Kiss, András; Liaudet, Lucas; Salomao, Reinaldo; Soriano, Francisco Garcia; Szabo, Csaba.

In: Pharmacological Research, Vol. 145, 104263, 01.07.2019.

Research output: Contribution to journalArticle

Ahmad, Akbar ; Vieira, Juliana de Camargo ; Haas de Mello, Aline ; de Lima, Thais Martins ; Ariga, Suely Kubo ; Barbeiro, Denise Frediani ; Barbeiro, Hermes Vieira ; Szczesny, Bartosz ; Törö, Gábor ; Druzhyna, Nadiya ; Randi, Elisa B. ; Marcatti, Michela ; Toliver-Kinsky, Tracy ; Kiss, András ; Liaudet, Lucas ; Salomao, Reinaldo ; Soriano, Francisco Garcia ; Szabo, Csaba. / The PARP inhibitor olaparib exerts beneficial effects in mice subjected to cecal ligature and puncture and in cells subjected to oxidative stress without impairing DNA integrity : A potential opportunity for repurposing a clinically used oncological drug for the experimental therapy of sepsis. In: Pharmacological Research. 2019 ; Vol. 145.
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abstract = "Poly(ADP-ribose)polymerase (PARP)is involved in the pathogenesis of cell dysfunction, inflammation and organ failure during septic shock. The goal of the current study was to investigate the efficacy and safety of the clinically approved PARP inhibitor olaparib in experimental models of oxidative stress in vitro and in sepsis in vivo. In mice subjected to cecal ligation and puncture (CLP)organ injury markers, circulating and splenic immune cell distributions, circulating mediators, DNA integrity and survival was measured. In U937 cells subjected to oxidative stress, cellular bioenergetics, viability and DNA integrity were measured. Olaparib was used to inhibit PARP. The results show that in adult male mice subjected to CLP, olaparib (1–10 mg/kg i.p.)improved multiorgan dysfunction. Olaparib treatment reduced the degree of bacterial CFUs. Olaparib attenuated the increases in the levels of several circulating mediators in the plasma. In the spleen, the number of CD4+ and CD8+ lymphocytes were reduced in response to CLP; this reduction was inhibited by olaparib treatment. Treg but not Th17 lymphocytes increased in response to CLP; these cell populations were reduced in sepsis when the animals received olaparib. The Th17/Treg ratio was lower in CLP-olaparib group than in the CLP control group. Analysis of miRNA expression identified a multitude of changes in spleen and circulating white blood cell miRNA levels after CLP; olaparib treatment selectively modulated these responses. Olaparib extended the survival rate of mice subjected to CLP. In contrast to males, in female mice olaparib did not have significant protective effects in CLP. In aged mice olaparib exerted beneficial effects that were less pronounced than the effects obtained in young adult males. In in vitro experiments in U937 cells subjected to oxidative stress, olaparib (1–100 μM)inhibited PARP activity, protected against the loss of cell viability, preserved NAD + levels and improved cellular bioenergetics. In none of the in vivo or in vitro experiments did we observe any adverse effects of olaparib on nuclear or mitochondrial DNA integrity. In conclusion, olaparib improves organ function and extends survival in septic shock. Repurposing and eventual clinical introduction of this clinically approved PARP inhibitor may be warranted for the experimental therapy of septic shock.",
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T1 - The PARP inhibitor olaparib exerts beneficial effects in mice subjected to cecal ligature and puncture and in cells subjected to oxidative stress without impairing DNA integrity

T2 - A potential opportunity for repurposing a clinically used oncological drug for the experimental therapy of sepsis

AU - Ahmad, Akbar

AU - Vieira, Juliana de Camargo

AU - Haas de Mello, Aline

AU - de Lima, Thais Martins

AU - Ariga, Suely Kubo

AU - Barbeiro, Denise Frediani

AU - Barbeiro, Hermes Vieira

AU - Szczesny, Bartosz

AU - Törö, Gábor

AU - Druzhyna, Nadiya

AU - Randi, Elisa B.

AU - Marcatti, Michela

AU - Toliver-Kinsky, Tracy

AU - Kiss, András

AU - Liaudet, Lucas

AU - Salomao, Reinaldo

AU - Soriano, Francisco Garcia

AU - Szabo, Csaba

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Poly(ADP-ribose)polymerase (PARP)is involved in the pathogenesis of cell dysfunction, inflammation and organ failure during septic shock. The goal of the current study was to investigate the efficacy and safety of the clinically approved PARP inhibitor olaparib in experimental models of oxidative stress in vitro and in sepsis in vivo. In mice subjected to cecal ligation and puncture (CLP)organ injury markers, circulating and splenic immune cell distributions, circulating mediators, DNA integrity and survival was measured. In U937 cells subjected to oxidative stress, cellular bioenergetics, viability and DNA integrity were measured. Olaparib was used to inhibit PARP. The results show that in adult male mice subjected to CLP, olaparib (1–10 mg/kg i.p.)improved multiorgan dysfunction. Olaparib treatment reduced the degree of bacterial CFUs. Olaparib attenuated the increases in the levels of several circulating mediators in the plasma. In the spleen, the number of CD4+ and CD8+ lymphocytes were reduced in response to CLP; this reduction was inhibited by olaparib treatment. Treg but not Th17 lymphocytes increased in response to CLP; these cell populations were reduced in sepsis when the animals received olaparib. The Th17/Treg ratio was lower in CLP-olaparib group than in the CLP control group. Analysis of miRNA expression identified a multitude of changes in spleen and circulating white blood cell miRNA levels after CLP; olaparib treatment selectively modulated these responses. Olaparib extended the survival rate of mice subjected to CLP. In contrast to males, in female mice olaparib did not have significant protective effects in CLP. In aged mice olaparib exerted beneficial effects that were less pronounced than the effects obtained in young adult males. In in vitro experiments in U937 cells subjected to oxidative stress, olaparib (1–100 μM)inhibited PARP activity, protected against the loss of cell viability, preserved NAD + levels and improved cellular bioenergetics. In none of the in vivo or in vitro experiments did we observe any adverse effects of olaparib on nuclear or mitochondrial DNA integrity. In conclusion, olaparib improves organ function and extends survival in septic shock. Repurposing and eventual clinical introduction of this clinically approved PARP inhibitor may be warranted for the experimental therapy of septic shock.

AB - Poly(ADP-ribose)polymerase (PARP)is involved in the pathogenesis of cell dysfunction, inflammation and organ failure during septic shock. The goal of the current study was to investigate the efficacy and safety of the clinically approved PARP inhibitor olaparib in experimental models of oxidative stress in vitro and in sepsis in vivo. In mice subjected to cecal ligation and puncture (CLP)organ injury markers, circulating and splenic immune cell distributions, circulating mediators, DNA integrity and survival was measured. In U937 cells subjected to oxidative stress, cellular bioenergetics, viability and DNA integrity were measured. Olaparib was used to inhibit PARP. The results show that in adult male mice subjected to CLP, olaparib (1–10 mg/kg i.p.)improved multiorgan dysfunction. Olaparib treatment reduced the degree of bacterial CFUs. Olaparib attenuated the increases in the levels of several circulating mediators in the plasma. In the spleen, the number of CD4+ and CD8+ lymphocytes were reduced in response to CLP; this reduction was inhibited by olaparib treatment. Treg but not Th17 lymphocytes increased in response to CLP; these cell populations were reduced in sepsis when the animals received olaparib. The Th17/Treg ratio was lower in CLP-olaparib group than in the CLP control group. Analysis of miRNA expression identified a multitude of changes in spleen and circulating white blood cell miRNA levels after CLP; olaparib treatment selectively modulated these responses. Olaparib extended the survival rate of mice subjected to CLP. In contrast to males, in female mice olaparib did not have significant protective effects in CLP. In aged mice olaparib exerted beneficial effects that were less pronounced than the effects obtained in young adult males. In in vitro experiments in U937 cells subjected to oxidative stress, olaparib (1–100 μM)inhibited PARP activity, protected against the loss of cell viability, preserved NAD + levels and improved cellular bioenergetics. In none of the in vivo or in vitro experiments did we observe any adverse effects of olaparib on nuclear or mitochondrial DNA integrity. In conclusion, olaparib improves organ function and extends survival in septic shock. Repurposing and eventual clinical introduction of this clinically approved PARP inhibitor may be warranted for the experimental therapy of septic shock.

KW - Cell death

KW - DNA

KW - Mitochondria

KW - Multiorgan dysfunction

KW - Sepsis

KW - Shock

KW - Th17

KW - Treg

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