Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy.
Int J Mol Sci. 2022 Jun 7;23(12):6375. doi: 10.3390/ijms23126375.
Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancer cases, causing a more aggressive tumour growth and poor prognosis. Trastuzumab, the humanized antibody targeted to HER2, increased the life expectancy of patients, but severe cardiotoxicity emerged as a long-term adverse effect. Clinical evidence highlights that Trastuzumab-induced cardiotoxicity drastically increases in association with Doxorubicin; however, the exact mechanisms involved remain incompletely understood. In order to analyse the molecular mechanisms involved and the possible adaptative responses to Trastuzumab and Doxorubicin treatment, in this study, H9c2 cardiomyoblasts were used. Results showed that Trastuzumab and Doxorubicin sequential administration in cardiomyoblast increased cytosolic and mitochondrial ROS production, intracellular calcium dysregulation, mitochondrial membrane depolarization, and the consequent apoptosis, induced by both Trastuzumab and Doxorubicin alone. Furthermore, in these conditions, we observed increased levels of Connexin43 phosphorylated on Ser368 (pCx43). Since phosphorylation on Ser368 decreases gap junction intracellular communication, thus reducing the spread of death signals to adjacent cells, we hypothesized that the increase in pCx43 could be an adaptative response implemented by cells to defend neighbouring cells by Trastuzumab and Doxorubicin sequential administration. However, the other side of the coin is the resulting conduction abnormalities.
人表皮生长因子受体-2（HER2）在多达 30%的乳腺癌病例中过表达，导致肿瘤生长更具侵袭性和预后不良。曲妥珠单抗是一种针对 HER2 的人源化抗体，它延长了患者的预期寿命，但严重的心脏毒性也成为了一种长期的不良反应。临床证据表明，曲妥珠单抗引起的心脏毒性与多柔比星密切相关；然而，具体的相关机制仍不完全清楚。为了分析涉及的分子机制以及曲妥珠单抗和多柔比星治疗可能产生的适应性反应，本研究使用了 H9c2 心肌细胞。结果表明，曲妥珠单抗和多柔比星序贯给药会增加心肌细胞内的 ROS 生成、细胞内钙离子失衡、线粒体膜去极化以及随后的细胞凋亡，这些作用与曲妥珠单抗和多柔比星单独作用的效果相似。此外，在这些条件下，我们观察到磷酸化的 Connexin43（pCx43）水平增加。由于 Ser368 位点的磷酸化会降低缝隙连接的细胞内通讯，从而减少死亡信号向相邻细胞的扩散，我们假设 pCx43 的增加可能是细胞对曲妥珠单抗和多柔比星序贯给药的适应性反应，通过这种方式保护邻近细胞。然而，硬币的另一面是由此导致的传导异常。
