Aldose reductase inhibitor, fidarestat prevents doxorubicin-induced endothelial cell death and dysfunction

Himangshu Sonowal, Pabitra Pal, Kirtikar Shukla, Ashish Saxena, Satish K. Srivastava, Kota Ramana

Research output: Contribution to journalArticle

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Abstract

Despite doxorubicin (Dox) being one of the most widely used chemotherapy agents for breast, blood and lung cancers, its use in colon cancer is limited due to increased drug resistance and severe cardiotoxic side effects that increase mortality associated with its use at high doses. Therefore, better adjuvant therapies are warranted to improve the chemotherapeutic efficacy and to decrease cardiotoxicity. We have recently shown that aldose reductase inhibitor, fidarestat, increases the Dox-induced colon cancer cell death and reduces cardiomyopathy. However, the efficacy of fidarestat in the prevention of Dox-induced endothelial dysfunction, a pathological event critical to cardiovascular complications, is not known. Here, we have examined the effect of fidarestat on Dox-induced endothelial cell toxicity and dysfunction in vitro and in vivo. Incubation of human umbilical vein endothelial cells (HUVECs) with Dox significantly increased the endothelial cell death, and pre-treatment of fidarestat prevented it. Further, fidarestat prevented the Dox-induced oxidative stress, formation of reactive oxygen species (ROS) and activation of Caspase-3 in HUVECs. Fidarestat also prevented Dox-induced monocyte adhesion to HUVECs and expression of ICAM-1 and VCAM-1. Fidarestat pre-treatment to HUVECs restored the Dox-induced decrease in the Nitric Oxide (NO)-levels and eNOS expression. Treatment of HUVECs with Dox caused a significant increase in the activation of NF-κB and expression of various inflammatory cytokines and chemokines which were prevented by fidarestat pre-treatment. Most importantly, fidarestat prevented the Dox-induced mouse cardiac cell hypertrophy and expression of eNOS, iNOS, and 3-Nitrotyrosine in the aorta tissues. Further, fidarestat blunted the Dox-induced expression of various inflammatory cytokines and chemokines in vivo. Thus, our results suggest that by preventing Dox-induced endothelial cytotoxicity and dysfunction, AR inhibitors could avert cardiotoxicity associated with anthracycline chemotherapy.

LanguageEnglish (US)
Pages181-190
Number of pages10
JournalBiochemical Pharmacology
Volume150
DOIs
StatePublished - Apr 1 2018

Fingerprint

Aldehyde Reductase
Endothelial cells
Cell death
Doxorubicin
Cell Death
Endothelial Cells
Human Umbilical Vein Endothelial Cells
Chemotherapy
Chemokines
Colonic Neoplasms
fidarestat
Chemical activation
Cytokines
Therapeutics
Drug Therapy
Oxidative stress
Vascular Cell Adhesion Molecule-1
Anthracyclines
Cardiomegaly
Intercellular Adhesion Molecule-1

Keywords

  • Aldose reductase
  • Cardiotoxicity
  • Doxorubicin
  • Endothelial cells
  • Fidarestat

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Aldose reductase inhibitor, fidarestat prevents doxorubicin-induced endothelial cell death and dysfunction. / Sonowal, Himangshu; Pal, Pabitra; Shukla, Kirtikar; Saxena, Ashish; Srivastava, Satish K.; Ramana, Kota.

In: Biochemical Pharmacology, Vol. 150, 01.04.2018, p. 181-190.

Research output: Contribution to journalArticle

Sonowal, Himangshu ; Pal, Pabitra ; Shukla, Kirtikar ; Saxena, Ashish ; Srivastava, Satish K. ; Ramana, Kota. / Aldose reductase inhibitor, fidarestat prevents doxorubicin-induced endothelial cell death and dysfunction. In: Biochemical Pharmacology. 2018 ; Vol. 150. pp. 181-190.
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