Abstract 2262: Anti-proliferative and cytotoxic activities of the anti-malarial compound artesunate for breast and ovarian cancer cell lines.

Abstract

Abstract Introduction: In women, breast cancer is the most prevalent cancer diagnosis while ovarian cancer represents the most lethal gynecological neoplasm. Together, these cancer types place a huge burden on society, comprising 20% of all estimated cancer deaths in the USA for 2012. The high incidence and mortality rates of these cancer types, in addition to the emergence of multi-drug resistant variants, highlights the need to develop novel therapeutic agents with greater efficacy. Artesunate (ART) is a semi-synthetic derivative of artemisinin, a natural compound derived from the Chinese herb Artemisia annua L. ART is an antimalarial agent that also possesses potent anticancer activity. Since the use of ART as an antimalarial agent is associated with few adverse effects, ART may represent a less toxic alternative to conventional chemotherapy. This study investigates the cytotoxic effects of ART on breast and ovarian cancer cell lines and the mechanisms underlying its activity. Methods & Results: ART exhibited a dose- and time-dependent effect on a panel of breast and ovarian cancer cell lines. Anticancer activity was also observed in 3-D cultures of both cancer cell types. Oregon Green 488 and propidium iodide (PI) staining of cancer cells revealed that ART strongly inhibited cancer cell proliferation, arresting cells in the G1 or G2 phases of the cell cycle. ART-mediated G2 arrest was dependent on reactive oxygen species (ROS), as in the presence of an antioxidant all cell lines arrested in G1. ART's antiproliferative effect was due in part to its ability to modulate the expression of cell cycle regulatory proteins including cyclin D3, p21, CDK4 and CDC25C. Annexin V/PI staining of ART-treated cancer cells revealed that ART induced ROS-dependent apoptosis in both breast and ovarian cancer cell lines. Pretreatment of cancer cells with a pan-caspase inhibitor decreased but did not eliminate ART-induced cytotoxicity, suggesting that caspase-dependent apoptosis is one of several pathways involved in ART-mediated killing of cancer cells. ART caused ROS-dependent DNA damage indicated by the presence of γH2AX, which implicates the DNA damage pathway in ART-induced cancer cell death. Annexin V/PI staining of ART-treated normal dermal fibroblasts and human mammary epithelial cells demonstrated that ART had limited cytotoxicity for normal cells at doses that were toxic to cancer cells, highlighting an increased sensitivity of cancer cells to ART treatment. Conclusions: These data show that ART has a potent antiproliferative and cytotoxic effect on both breast and ovarian cancer cells with limited cytotoxicity for normal cells. ART's specific cytotoxic activity and excellent safety record in malaria patients make it a worthy candidate for further investigation as a possible treatment for breast and ovarian cancer. Supported by NSERC and the CBCF-Atlantic Region Citation Format: Anna L. Greenshields, David Hoskin. Anti-proliferative and cytotoxic activities of the anti-malarial compound artesunate for breast and ovarian cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2262. doi:10.1158/1538-7445.AM2013-2262