Oroxin A inhibits breast cancer cell growth by inducing robust endoplasmic reticulum stress and senescence

Abstract

Breast cancer is a major cause of cancer death among women. Although various anticancer drugs have been used in clinics, drugs that are effective against advanced and metastatic breast cancer are still lacking and in great demand. In this study, we found that oroxin A, an active component isolated from the herb Oroxylum indicum (L.) Kurz, effectively inhibited the growth of human breast cancer cells MDA-MB-231 and MCF7 by inducing endoplasmic reticulum (ER) stress-mediated senescence. Oroxin A caused breast cancer cell cycle arrest at the G2/M stage, and reorganization of microtubules and actin cytoskeleton accompanied by a decrease in cellular mitosis. ER-specific probe ER-Tracker Red and confocal microscope imaging showed that ER-Tracker Red-positive cells increased in an oroxin A dosage-dependent manner. In addition, oroxin A increased cell population with high β-Gal activity and SAHF-positive staining; these data suggest that oroxin A induces breast cancer cell ER stress and senescence. Mechanistic studies showed that oroxin A led to a significant increase in intracellular reactive oxygen species levels, promoted expression of ER stress markers ATF4 and GRP78, and increased the phosphorylation of a key stress-response signaling protein p38, resulting in an ER stress-mediated senescence. Taken together, our data indicate that oroxin A exerts its antibreast cancer effects by inducing ER stress-mediated senescence, activating the key stress p38 signaling pathway, and increasing key ER stress genes ATF4 and GRP78 expression levels.

Trichostatin A induces p53‑dependent endoplasmic reticulum stress in human colon cancer cells

“…TSA-induced apoptosis is an important function for cancer therapy; p53 has been identified to influence the antitumor effect of TSA (4). Tumor cells experience constant ER stress and are exposed to various stress stimuli in their microenvironment, including the accumulation of misfolded proteins, hypoxia, acidic pH levels, reactive oxygen species, calcium imbalance, viral proteins and hypoglycemia (23). Therefore, substantial ER stress may easily be induced in tumor cells, which may lead to tumor cell death.…”

Host–guest interaction of cucurbit[8]uril with oroxin A and its effect on the properties of oroxin A

“…Oroxin A (OA, baicalein-7-O-glucoside, Figure 1A) is one of the active ingredients isolated from the traditional herbal medi- cine Oroxylum indicum (L.) Kurz of Asian countries [23,24]. Accumulating studies have shown the beneficial biological effects of OA, which include antioxidant, antidiabetic, anticancer, antibacterial, anti-inflammatory and antiviral properties [25][26][27][28][29][30]. Herein, we selected Q [8] as a host molecule and investigated its host-guest interactions with OA, as well as its effect on the properties of OA.…”

Natural Polyphenols Targeting Senescence: A Novel Prevention and Therapy Strategy for Cancer

“…ER stress plays an important role in polyphenol-mediated cell senescence (Figures 3 and 4). An active flavonoid component oroxin A, which is obtained from the traditional Chinese herb Oroxylum indicum (L.) Kurz, increased ER-Tracker Red-positive cell population and upregulated ER stress-related proteins activating transcription factor 4 (ATF4) and binding immunoglobulin protein (GRP78), caused cell cycle arrest at the G2/M phase and induced senescence in human breast cancer cells while p38-specific inhibitor SB203580 blocked ER stress induced senescence [79]. Cristacarpin, a known isoflavonoid isolated from Erythrina suberosa stem bark, enhanced ER stress with increased expressions of GRP-94 and PERK by activation of p38, thereby generating sub-lethal ROS, elevating the expression of p21 waf1 in a p53-independent manner, and reducing the expressions of Cdk-2 and cyclinD1, which in turn caused cellular senescence through G1 phase cell cycle arrest in pancreatic and breast cancer cells [80].…”