The anti-malarial drug artesunate causes cell cycle arrest and apoptosis of triple-negative MDA-MB-468 and HER2-enriched SK-BR-3 breast cancer cells

• Published in: Experimental and molecular pathology Vol. 107; pp. 10 - 22
• Main Authors: Greenshields, Anna L., Fernando, Wasundara, Hoskin, David W.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.04.2019
• Subjects: Artesunate; Cell cycle arrest; Cytotoxicity, Breast cancer, Reactive oxygen species; Cell cycle arrest; Cytotoxicity, Breast cancer, Reactive oxygen species; Artesunate
• ISSN: 0014-4800; 1096-0945; 1096-0945
• DOI: 10.1016/j.yexmp.2019.01.006

Breast cancer is the most prevalent cancer diagnosis in women, with triple-negative and human epidermal growth factor 2 (HER2)-enriched advanced breast cancers having the poorest prognoses. The morbidity and mortality associated with advanced disease, as well as the emergence of multi-drug resistant variants, highlights the urgency to develop novel therapeutic agents. Artesunate (ART) is a semi-synthetic derivative of artemisinin from the Chinese herb sweet wormwood. ART is widely used in the treatment of malaria and is well tolerated by patients. Importantly, ART also has anti-cancer activities and may therefore represent a less toxic alternative to conventional chemotherapy. In this study, we demonstrate a dose- and time-dependent inhibitory effect of ART on the growth of triple-negative MDA-MB-468 and HER2-enriched SK-BR-3 breast cancer cells, which was the result of both anti-proliferative and cytotoxic activities. ART inhibited breast cancer cell proliferation via a reactive oxygen species (ROS)-dependent G2/M arrest and ROS-independent G1 arrest. ART-treated MDA-MB-468 and SK-BR-3 cells also experienced apoptotic cell death, which was both ROS- and iron-dependent. ART-induced oxidative stress caused the loss of mitochondrial outer membrane integrity and damage to the cellular DNA of MDA-MB-468 and SK-BR-3 cells. In addition, exposure to low-dose ART sensitized MDA-MB-468 and SK-BR-3 cells to chemotherapeutic drugs. On the basis of our findings, we suggest that ART may have clinical utility in the treatment of triple-negative and HER2-enriched breast cancers. •Artesunate inhibits triple-negative and HER2-enriched breast cancer cell growth.•Artesunate induces reactive oxygen species (ROS) in breast cancer cells.•Artesunate-induced apoptosis is selective for breast cancer cells.•Artesunate-induced apoptosis is ROS- and iron-independent.