Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, China.
Department of Experimental Pharmacology and Toxicology, School of pharmaceutical science, Jilin University, Changchun, China.
Clinics (Sao Paulo). 2023 Aug 9;78:100268. doi: 10.1016/j.clinsp.2023.100268. eCollection 2023.
Trastuzumab is the preferred drug for the treatment of breast cancer. However, research on the cellular mechanisms of trastuzumab's potential cardiotoxicity is insufficient. The purpose of this study was to explore the toxic effects and potential mechanism of action of trastuzumab on cardiomyocytes.
Human Cardiomyocyte (HCM) viability was assessed using the MTT method. HCM apoptosis was detected using the Hoechst33342/PI Fluorescent staining. The LDH and CK activities of the cell were measured using commercially available LDH and CK assay kits. The expression levels of Notch2, JAK2, STAT3, cleaved caspase 3, bax, and bcl 2 in HCMs were detected using western blotting.
The results showed that 250 mg/L trastuzumab induced cardiomyocyte injury and apoptosis, inhibited viability, activated the Notch2 receptor, and inhibited JAK2/STAT3 expression in HCM. Inhibition of Notch2 expression in HCM by targeted siNotch2 transfection reversed the trastuzumab-induced injury and apoptosis, and the expression of JAK2/STAT3 returned to normal levels.
Trastuzumab induces Notch2 expression by inhibiting the JAK2/STAT3 pathway of HCMs, promotes cell apoptosis, and causes cardiomyocyteinjury. Notch2 may be a potential target of trastuzumab-inducedmyocardial injury. This experiment reveals the mechanism of trastuzumab-induced cardiotoxicity, providing a theoretical basis for the application of trastuzumab.
曲妥珠单抗是治疗乳腺癌的首选药物。然而，关于曲妥珠单抗潜在心脏毒性的细胞机制研究还不够充分。本研究旨在探讨曲妥珠单抗对心肌细胞的毒性作用及潜在作用机制。
采用 MTT 法检测人心肌细胞（HCM）活力。采用 Hoechst33342/PI 荧光染色法检测 HCM 细胞凋亡。采用商用 LDH 和 CK 测定试剂盒检测细胞中 LDH 和 CK 活性。采用 Western blot 检测 HCM 中 Notch2、JAK2、STAT3、cleaved caspase 3、bax 和 bcl-2 的表达水平。
结果表明，250mg/L 曲妥珠单抗诱导心肌细胞损伤和凋亡，抑制细胞活力，激活 HCM 中的 Notch2 受体，并抑制 JAK2/STAT3 表达。通过靶向 siNotch2 转染抑制 HCM 中的 Notch2 表达，逆转了曲妥珠单抗诱导的损伤和凋亡，JAK2/STAT3 的表达恢复正常水平。
曲妥珠单抗通过抑制 HCM 的 JAK2/STAT3 通路诱导 Notch2 表达，促进细胞凋亡，导致心肌细胞损伤。Notch2 可能是曲妥珠单抗诱导心肌损伤的潜在靶点。该实验揭示了曲妥珠单抗诱导心脏毒性的机制，为曲妥珠单抗的应用提供了理论依据。
