Doxorubicin‐induced normal breast epithelial cellular aging and its related breast cancer growth through mitochondrial autophagy and oxidative stress mitigated by ginsenoside Rh2

• Published in: Phytotherapy research Vol. 34; no. 7; pp. 1659 - 1669
• Main Authors: Hou, Jingang, Yun, Yeejin, Xue, Jianjie, Jeon, Byeongmin, Kim, Sunchang
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.07.2020; Wiley Subscription Services, Inc
• Subjects: Age related diseases; Aging; Antibodies; Attenuation; Autophagy; Breast cancer; cancer growth; Cell culture; Cell proliferation; cellular senescence; chemotherapy; Doxorubicin; Epithelial cells; ginsenoside Rh2; Ginsenosides; Health services; Mitochondria; mitophagy; Oxidative stress; Parkin protein; Phagocytosis; Phenotypes; PTEN-induced putative kinase; Reactive oxygen species; ROS; Senescence; Superoxide dismutase; Therapeutic applications; TRAF6 protein; Western blotting; mitophagy; cellular senescence; ginsenoside Rh2; chemotherapy; cancer growth; ROS
• ISSN: 0951-418X; 1099-1573
• DOI: 10.1002/ptr.6636

Clinical dose of doxorubicin (100 nM) induced cellular senescence and various secretory phenotypes in breast cancer and normal epithelial cells. Herein, we reported the detailed mechanism underlying ginsenoside Rh2‐mediated NF‐κB inhibition, and mitophagy promotion were evaluated by antibody array assay, western blotting analysis, and immunocytostaining. Ginsenoside Rh2 suppressed the protein levels of TRAF6, p62, phosphorylated IKK, and IκB, which consequently inactivated NF‐κB activity. Rh2‐mediated secretory phenotype was delineated by the suppressed IL‐8 secretion. Senescent epithelial cells showed increased level of reactive oxygen species (ROS), which was significantly abrogated by Rh2, with upregulation on SIRT 3 and SIRT 5 and subsequent increase in SOD1 and SOD2. Rh2 remarkably favored mitophagy by the increased expressions of PINK1 and Parkin and decreased level of PGC‐1α. A decreased secretion of IL‐8 challenged by mitophagy inhibitor Mdivi‐1 with an NF‐κB luciferase system was confirmed. Importantly, secretory senescent epithelial cells promoted the breast cancer (MCF‐7) proliferation while decreased the survival of normal epithelial cells demonstrated by co‐culture system, which was remarkably alleviated by ginsenoside Rh2 treatment. These data included ginsenoside Rh2 regulated ROS and mitochondrial autophagy, which were in large part attributed to secretory phenotype of senescent breast epithelial cells induced by doxorubicin. These findings also suggested that ginsenoside Rh2 is a potential treatment candidate for the attenuation of aging related disease. Cellular senescence plays a vital role in aging and aging‐related pathologies. Clinical dose of Doxorubicin induced cellular senescence of human normal epithelial cells. Interestingly, ginsenoside Rh2 selectively regulated the detrimental effects of the chemoinduced secretory senescence via mitophagy and ROS, which subsequent suppressed senescence‐associated breast tumor growth. These findings proposed ginsenoside Rh2 as a therapeutic candidate for the potential aging and aging‐related diseases.