Inhibition of Cell Growth and Induction of Apoptosis byAntrodia camphoratain HER-2/neu-Overexpressing Breast Cancer Cells through the Induction of ROS, Depletion of HER-2/neu, and Disruption of the PI3K/Akt Signaling Pathway

Abstract

Previously, we demonstrated that a submerged fermentation culture of Antrodia camphorata (AC) promotes cell-cycle arrest and apoptosis in human estrogen receptor-positive/negative breast cancer cells. However, whether AC is effective against HER-2/neu-overexpressing breast cancers has not been thoroughly elucidated. In the present study, we showed that AC exhibited a significant cytotoxic effect against HER-2/neu-overexpressing MDA-MB-453 and BT-474 cells. Immunoblot analysis demonstrated that HER-2/neu and their tyrosine phosphorylation were inhibited by AC in a dose-dependent manner. An increase in intracellular reactive oxygen species (ROS) was observed in AC-treated cells, whereas antioxidant N-acetylcysteine (NAC) significantly prevented AC induced HER-2/neu depletion and cell death, which directly indicates that AC-induced HER-2/neu depletion and cell death was mediated by ROS generation. Also, AC significantly downregulated the expression of cyclin D1, cyclin E, and CDK4 followed by the suppression of PI3K/Akt, and their downstream effectors GSK-3β and β-catenin. Notably, AC-treatment induced apoptotic cell death, which was associated with sub-G1 accumulation, DNA fragmentation, mitochondrial dysfunction, cytochrome c release, caspase-3/-9 activation, PARP degradation, and Bcl-2/Bax dysregulation. Assays for colony formation also confirmed the growth-inhibitory effects of AC. This is the first report confirming the anticancer activity of this potentially beneficial mushroom against human HER-2/neu-overexpressing breast cancers.

Coenzyme Q0 from Antrodia cinnamomea in Submerged Cultures Induces Reactive Oxygen Species‐Mediated Apoptosis in A549 Human Lung Cancer Cells

“…CoQ0 may induce the opening of mitochondrial permeability transition pore (PTP) and the production of H 2 O 2 as previously described [32, 33]. Similar to our findings, ROS was also shown to mediate apoptosis of HER-2/neu-overexpressing breast cancer cells induced by the culture broth of A. cinnamomea [34]. We found that CoQ0 exerts a higher cytotoxicity in A549 cancer cells (IC 50 ≈ 15  μ g/mL) than in normal human fibroblast Detroit 551 cells (IC 50 ≈ 42  μ g/mL, data not shown).…”

Regulation of the FOXO3a/Bim signaling pathway by 5,7-dihydroxy-8-nitrochrysin in MDA-MB-453 breast cancer cells

“…Apoptotic resistance in HER-2/neu-overexpressing breast cancer cells is mediated by a loss of FOXO3a activity (25) and we demonstrated that this pathway is inhibited by NOC. Upstream, NOC activates FOXO3a by targeting the Akt pathway.…”

Radioprotective effects ofAntrodia cinnamomeaare enhanced on immune cells and inhibited on cancer cells

“…HT-29 cells pretreated with AC539 showed an increase in IL-1 β expression after radiation treatment, whereas expression of iNOS and TNF-α were decreased after 24-h AC539 pretreatment, and their expression increased in a dose-dependent manner after 48-h AC539 pretreatment ( Figure 5A). Th is eff ect was more obvious in the radiosensitive BT-474 cells ( Figure 5B), apoptosis induction (Lee et al 2012). In radiation therapy, tumor hypoxia is a common cause for treatment failure.…”