Nodakenin Induces ROS-Dependent Apoptotic Cell Death and ER Stress in Radioresistant Breast Cancer

Angelica gigas exerts powerful anti-tumor and anti-cancer effects in various cancer cell types. However, there have been few studies regarding the anti-cancer effect of nodakenin, a bioactive compound of Angelica gigas, in vivo and in vitro on breast cancers. I found that nodakenin, in a concentration-dependent manner, inhibits breast cancer cell viability and decreases the tumor volume in mice. Additionally, nodakenin induces caspase-3-dependent apoptosis in breast cancer cells; however, the combination of Z-VAD-FMK and nodakenin suppresses the caspase-3-dependent apoptotic cell death. Furthermore, nodakenin mediates apoptotic cell death via the PERK-mediated signaling pathway and calcium (Ca2+) release, and nodakenin combined with thapsigargin induces synergistic cell death by inhibiting sarco/endoplasmic reticulum (ER) Ca2+-ATPase. However, knockdown of PERK or CHOP inhibits Ca2+ generation and caspase-dependent apoptosis in nodakenin-treated breast cancer cells. Nodakenin induces ROS and Ca2+ generation, ER stress, and apoptotic cell death; however, the knockdown of Nox4 inhibits ROS generation and ER stress- and caspase-dependent apoptotic cell death. In addition, nodakenin combined with radiation overcomes radioresistance in radioresistant breast cancer cells by suppressing epithelial-mesenchymal transition phenotypes, including the decrease in E-cadherin and the increase in N-cadherin and vimentin. Therefore, these findings indicate that nodakenin may be a novel therapeutic strategy for breast cancers.

Automated summary

Angelica gigas has a potent anti-tumor and anti-cancer effect. This study focused on the bioactive compound nodakenin and its effects on breast cancer. Nodakenin was found to inhibit breast cancer cell viability, decrease tumor volume in mice, and induce apoptosis. It also affected signaling pathways and calcium release. Additionally, nodakenin combined with radiation overcame radioresistance in breast cancer cells. These findings suggest nodakenin as a potential therapeutic strategy for breast cancer.