Dapagliflozin protects against doxorubicin-induced nephrotoxicity associated with nitric oxide pathway—A translational study

Wei Ting Chang, Chia Chun Wu, I. Chuang Liao, Yu Wen Lin, Yi Chen Chen, Chung Han Ho, Wei Chieh Lee, You Cheng Lin, Zhih Cherng Chen, Jhih Yuan Shih, Nan Chun Wu, Wei Chih Kan

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Doxorubicin (Dox) is a potent anticancer agent, but its associated organ toxicity, including nephrotoxicity, restricts clinical applications. Dapagliflozin (DAPA), a sodium–glucose cotransporter-2 inhibitor, has been shown to slow the progression of kidney disease in patients with and without diabetes. However, the effect of DAPA to counteract Dox-induced nephrotoxicity remains uncertain. Therefore, in this study, we aimed to elucidate the effects of DAPA in mitigating Dox-induced nephrotoxicity. We analyzed the Taiwan National Health Insurance Database to evaluate the incidence of renal failure among breast cancer patients receiving Dox treatment compared to those without. After adjusting for age and comorbidities, we found that the risk of renal failure was significantly higher in Dox-treated patients (incidence rate ratio, 2.45; confidence interval, 1.41–4.26; p = 0.0014). In a parallel study, we orally administered DAPA to Sprague–Dawley rats for 6 weeks, followed by Dox for 4 weeks. DAPA ameliorated Dox-induced glomerular atrophy, renal fibrosis, and dysfunction. Furthermore, DAPA effectively suppressed Dox-induced apoptosis and reactive oxygen species production. On a cellular level, DAPA in HK-2 cells mitigated Dox-mediated suppression of the endothelial NOS pathway and reduced Dox-induced activities of reactive oxygen species and apoptosis-associated proteins. DAPA improved Dox-induced apoptosis and renal dysfunction, suggesting its potential utility in preventing nephrotoxicity in patients with cancer undergoing Dox treatment.

Original languageEnglish
Pages (from-to)103-111
Number of pages9
JournalFree Radical Biology and Medicine
Volume208
DOIs
Publication statusPublished - 2023 Nov 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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