Resveratrol and FGF1 Synergistically Ameliorates Doxorubicin-Induced Cardiotoxicity via Activation of SIRT1-NRF2 Pathway

Nutrients. 2022 Sep 27;14(19):4017. doi: 10.3390/nu14194017.


Doxorubicin (DOX) has received attention due to dose-dependent cardiotoxicity through abnormal redox cycling. Native fibroblast growth factor 1 (FGF1) is known for its anti-oxidative benefits in cardiovascular diseases, but possesses a potential tumorigenic risk. Coincidentally, the anti-proliferative properties of resveratrol (RES) have attracted attention as alternatives or auxiliary therapy when combined with other chemotherapeutic drugs. Therefore, the purpose of this study is to explore the therapeutic potential and underlying mechanisms of co-treatment of RES and FGF1 in a DOX-treated model. Here, various cancer cells were applied to determine whether RES could antagonize the oncogenesis effect of FGF1. In addition, C57BL/6J mice and H9c2 cells were used to testify the therapeutic potential of a co-treatment of RES and FGF1 against DOX-induced cardiotoxicity. We found RES could reduce the growth-promoting activity of FGF1. Additionally, the co-treatment of RES and FGF1 exhibits a more powerful cardio-antioxidative capacity in a DOX-treated model. The inhibition of SIRT1/NRF2 abolished RES in combination with FGF1 on cardioprotective action. Further mechanism analysis demonstrated that SIRT1 and NRF2 might form a positive feedback loop to perform the protective effect on DOX-induced cardiotoxicity. These favorable anti-oxidative activities and reduced proliferative properties of the co-treatment of RES and FGF1 provided a promising therapy for anthracycline cardiotoxicity during chemotherapy.

Keywords: NRF2; SIRT1; cardiotoxicity; doxorubicin; oxidative stress.

MeSH terms

  • Animals
  • Apoptosis
  • Cardiotoxicity* / drug therapy
  • Doxorubicin / toxicity
  • Fibroblast Growth Factor 1* / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac
  • NF-E2-Related Factor 2* / metabolism
  • Oxidative Stress
  • Resveratrol* / pharmacology
  • Sirtuin 1* / metabolism


  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Fibroblast Growth Factor 1
  • Doxorubicin
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Resveratrol