Ginsenoside Rh2 mitigates doxorubicin-induced cardiotoxicity by inhibiting apoptotic and inflammatory damage and weakening pathological remodelling in breast cancer-bearing mice

Rh2 regulates multiple pathways in the Dox-provoked heart, proposing a potential candidate for cancer supplement and therapy-associated cardiotoxicity.

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. Conclusions: Rh2 regulates multiple pathways in the Dox-provoked heart, proposing a potential candidate for cancer supplement and therapy-associated cardiotoxicity.