PTUPB, a soluble epoxide hydrolase/cyclooxygenase‑2 dual inhibitor, reduces endothelial‑to‑mesenchymal transition and improves doxorubicin‑induced vascular and cardiac toxicity.

Doxorubicin (DOX) is an effective anthracycline agent used to combat a number of neoplastic diseases. However, DOX causes cardiovascular toxicity in juvenile and young adult survivors of cancer that can lead to future cardiomyopathy. Thus, it is important to address the cardiovascular toxicity caused by DOX to improve the long‑term health of patients with cancer. Soluble epoxide hydrolase (sEH) and cyclooxygenase‑2 (COX‑2) are implicated in cardiovascular diseases by impairing vascular health and promoting the transition of endothelial cells to mesenchymal cells. Given the role of sEH and COX‑2 in endothelial‑to‑mesenchymal transition (EndMT)‑derived cardiovascular toxicity, the present study aimed to investigate the effect of a dual sEH/COX‑2 inhibitor, 4‑[5‑phenyl‑3‑[3‑[[[[4‑(trifluoromethyl)phenyl] amino]carbonyl]amino]propyl]‑1H‑pyrazol‑1‑yl]‑benzenesulfonamide (PTUPB), on DOX‑induced EndMT‑derived vascular and cardiac toxicity. The mitigating effect of PTUPB on DOX‑induced cardiovascular toxicity was explored in zebrafish. The cardiovascular parameters were measured using the Viewpoint MicroZebralab software. Additionally, the effect of PTUPB on DOX‑induced EndMT was assessed in human endothelial cells. The data from the present study indicated that the inhibition of sEH and COX‑2 using PTUPB reduced DOX‑induced EndMT and vascular toxicity. The data also demonstrated that PTUPB improved cardiac function and morphology in zebrafish incubated with DOX. The results of the present study showed that PTUPB downregulated inflammation and oxidative stress markers, which contributed to the improvement in DOX‑induced cardiovascular toxicity. In conclusion, the findings of the present study indicated that the suppression of sEH/COX‑2 using PTUPB reduced DOX‑induced EndMT and the resulting vascular and cardiac toxicity.