Intelligent Synthetic Biology Center, Daejeon, Republic of Korea.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Cell Prolif. 2022 Jun;55(6):e13246. doi: 10.1111/cpr.13246. Epub 2022 May 9.
There are presently a few viable ways to reduce cardiotoxicity of doxorubicin (Dox). The combination of chemotherapy agents with natural compounds delivers greater efficacy and reduces adverse effects in recent researches for cancer treatment. Here, we examined the potential effect of ginsenoside Rh2 on a Dox-based regimen in chemotherapy treatment.
Human breast tumour (MDA-MB-231) xenograft nude mice, human cardiac ventricle fibroblasts, and human umbilical vein endothelial cells (HUVEC) were employed in the present study. Histology, immunohistochemistry, immunofluorescence, western blot, antibody array, and RNA-sequencing analyses were utilized to assess the protective effect of Rh2 on cardiotoxicity induced by Dox and the underlying mechanisms.
Rh2-reduced cardiotoxicity by inhibiting the cardiac histopathological changes, apoptosis and necrosis, and consequent inflammation. Pathological remodelling was attenuated by reducing fibroblast to myofibroblast transition (FMT) and endothelial-mesenchymal transition (EndMT) in hearts. RNA-sequencing analysis showed that Dox treatment predominantly targets cell cycle and attachment of microtubules and boosted tumour necrosis, chemokine and interferon-gamma production, response to cytokine and chemokine, and T cell activation, whereas Rh2 regulated these effects. Intriguingly, Rh2 also attenuated fibrosis via promoting senescence in myofibroblasts and reversing established myofibroblast differentiation in EndMT.
Rh2 regulates multiple pathways in the Dox-provoked heart, proposing a potential candidate for cancer supplement and therapy-associated cardiotoxicity.
目前有几种可行的方法可以降低多柔比星（Dox）的心脏毒性。在最近的癌症治疗化疗研究中，化疗药物与天然化合物的联合使用可以提高疗效，降低不良反应。在这里，我们研究了人参皂苷 Rh2 对基于 Dox 的化疗方案在化疗治疗中的潜在作用。
本研究使用了人乳腺癌（MDA-MB-231）异种移植裸鼠、人心房成纤维细胞和人脐静脉内皮细胞（HUVEC）。采用组织学、免疫组织化学、免疫荧光、western blot、抗体阵列和 RNA 测序分析评估 Rh2 对 Dox 诱导的心脏毒性的保护作用及其潜在机制。
Rh2 通过抑制心脏组织病理学变化、凋亡和坏死以及随后的炎症来减轻心脏毒性。通过减少心脏中的成纤维细胞向肌成纤维细胞转化（FMT）和内皮-间充质转化（EndMT），减轻病理性重塑。RNA 测序分析表明，Dox 治疗主要靶向细胞周期和微管附着，并促进肿瘤坏死、趋化因子和干扰素-γ的产生、对细胞因子和趋化因子的反应以及 T 细胞激活，而 Rh2 调节了这些效应。有趣的是，Rh2 还通过促进肌成纤维细胞衰老和逆转 EndMT 中已建立的肌成纤维细胞分化来减轻纤维化。
Rh2 调节了 Dox 引起的心脏中的多个途径，为癌症补充剂和治疗相关的心脏毒性提供了一个潜在的候选药物。
