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<p>5-fluorouracil (5-FU), a commonly utilized antitumor agent for the treatment of colon cancer, is linked to an increased risk of cardiovascular diseases. Antihistamines including astemizole (AST) have been reported to present cardiovascular toxicity; however, it remains unclear how 5-FU-mediated cardiotoxicity is affected by AST during the treatment of colon cancer. This study explored the role of AST in 5-FU-induced cardiotoxicity in colon cancer. 5-FU was used to induce cardiotoxicity in cardiomyocytes (HL-1 cells) and BALBc mice, creating in vitro and in vivo models of chemotherapeutic drug-induced cardiotoxicity. In the mice model, we found that the blocking of histamine signal by AST aggravated 5-FU-induced cardiac function injury and cardiac fibrosis. In HL-1 cardiomyocyte cells, the increases of apoptosis and generation of mitochondrial reactive oxygen species (mtROS) were evaluated after the combination treatment of AST and 5-FU. Proinflammatory M1-like-type macrophages were dominant in the AST and 5-FU combination group compared to control groups. The protein expression of prostaglandin-endoperoxide synthase 2 (Ptgs2) was assessed both in vitro and in vivo using Western blot analysis. Clinically, altered Ptgs2 was closely associated with adverse cardiovascular outcomes. Overall, the combination of AST and 5-FU significantly enhanced cardiotoxicity by inducing cardiomyocyte apoptosis, inflammation, and the expression of Ptgs2.</p>

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Astemizole Exacerbates 5-Fluorouracil-Triggered Cardiotoxicity by Enhancing Ptgs2

  • 期刊论文

  • 发表日期：

    2025年1月8日

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  • Mengshi Xie,
  • Pan Jiang,
  • Xiyang Yang,
  • Dili Sun,
  • Baoling Zhu,
  • Xiaowei Zhu,
  • Suling Ding,
  • Jian Gao,
  • Xiangdong Yang,
  • Hongyu Shi

摘要

5-fluorouracil (5-FU), a commonly utilized antitumor agent for the treatment of colon cancer, is linked to an increased risk of cardiovascular diseases. Antihistamines including astemizole (AST) have been reported to present cardiovascular toxicity; however, it remains unclear how 5-FU-mediated cardiotoxicity is affected by AST during the treatment of colon cancer. This study explored the role of AST in 5-FU-induced cardiotoxicity in colon cancer. 5-FU was used to induce cardiotoxicity in cardiomyocytes (HL-1 cells) and BALBc mice, creating in vitro and in vivo models of chemotherapeutic drug-induced cardiotoxicity. In the mice model, we found that the blocking of histamine signal by AST aggravated 5-FU-induced cardiac function injury and cardiac fibrosis. In HL-1 cardiomyocyte cells, the increases of apoptosis and generation of mitochondrial reactive oxygen species (mtROS) were evaluated after the combination treatment of AST and 5-FU. Proinflammatory M1-like-type macrophages were dominant in the AST and 5-FU combination group compared to control groups. The protein expression of prostaglandin-endoperoxide synthase 2 (Ptgs2) was assessed both in vitro and in vivo using Western blot analysis. Clinically, altered Ptgs2 was closely associated with adverse cardiovascular outcomes. Overall, the combination of AST and 5-FU significantly enhanced cardiotoxicity by inducing cardiomyocyte apoptosis, inflammation, and the expression of Ptgs2.