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

Abstract

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.

Oxidative Stress and Ginsenosides: An Update on the Molecular Mechanisms

“…20( R )-Rg3 reduced MDA levels and increased SOD and CAT production through a mechanism related to inhibition of the MAPK/NF- κ B signaling pathway. Hou et al [ 109 ] studied the effects of ginsenoside Rh2 on adriamycin-induced cell senescence in breast cancer and normal epithelial cells and confirmed that ginsenoside Rh2 reduced ROS production, increased SOD expression, reduced oxidative stress, and inhibited the NF- κ B signaling pathway in senescent cells. Chen et al [ 107 ] found that ginsenoside Rg3 can reduce TNF- α -induced damage to human NPCs by blocking the NF- κ B signaling pathway.…”

Effects of Traditional Chinese Medication‐Based Bioactive Compounds on Cellular and Molecular Mechanisms of Oxidative Stress

“…Ginsenoside, a potential treatment candidate for the attenuation of aging-related disease [87], produces antidepressant-like effects on chronic unpredictable mild stress-exposed rats involving protection against oxidative stress and thus the neuronal deterioration resulting from inflammatory responses [88]. Ginsenoside not only upregulates GPX4 to reduce oxidative stress and thereby alleviates 6-hydroxydopamine-induced neuronal damage [89] but also effectively attenuates D-galactose-induced oxidative stress via restoring the upstream PI3K/AKT signaling pathway [90].…”

Versatile role of curcumin and its derivatives in lung cancer therapy

“…However, the emergence of resistance has limited the potential of chemotherapy. Doxorubicin (DOX) is one of the effective chemotherapeutic compounds that restricts cancer proliferation by inhibiting microtubule disassembly (Hou, Yun, Xue, Jeon, & Kim, 2020). This agent is extensively applied in treatment of lung cancer (E. S. Lee et al, 2020).…”