title: Contribution of reactive oxygen species to ovarian cancer cell growth arrest and killing by the anti-malarial drug artesunate.
abstract: Ovarian cancer is a leading cause of cancer-related death in women and the most lethal gynecological malignancy in the developed world. The morbidity and mortality of ovarian cancer underscore the need for novel treatment options. Artesunate (ART) is a well-tolerated anti-malarial drug that also has anti-cancer activity. In this study, we show that ART inhibited the in vitro growth of a panel of ovarian cancer cell lines, as well as the growth of ovarian cancer cells isolated from patients. Moreover, ART decreased tumor growth in vivo in a mouse model of ovarian cancer. ART-treated ovarian cancer cells showed a strong induction of reactive oxygen species (ROS) and reduced proliferation. ROS-dependent cell cycle arrest occurred in the G2/M phase whereas ROS-independent cell cycle arrest occurred in the G1 phase, depending on the concentration of ART to which ovarian cancer cells were exposed. The anti-proliferative effect of ART was associated with altered expression of several key cell cycle regulatory proteins, including cyclin D3, E2F-1, and p21, as well as inhibition of mechanistic target of rapamycin signaling. Exposure of ovarian cancer cells to higher concentrations of ART resulted in ROS-dependent DNA damage and cell death. Pretreatment of ovarian cancer cells with a pan-caspase inhibitor or ferroptosis inhibitor decreased but did not completely eliminate ART-mediated cytotoxicity, suggesting the involvement of both caspase-dependent and caspase-independent pathways of killing. These data show that ART has potent anti-proliferative and cytotoxic effects on ovarian cancer cells, and may therefore be useful in the treatment of ovarian cancer. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Greenshields
authors.affiliation: Department of Obstetrics and Gynecology, University of Western Ontario, London, Ontario, Canada.|Department of Oncology, University of Western Ontario, London, Ontario, Canada.|Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Shepherd
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Hoskin
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use*; D000077332:Artesunate; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D037621:Artemisinins; D017382:Reactive Oxygen Species; D000077332:Artesunate
keywords: artesunate; cell cycle arrest; cytotoxicity; ovarian cancer; reactive oxygen species