STUDIES ON THE ANTI-CANCER PROPERTIES OF ARTESUNATE: ANTI-PROLIFERATIVE AND CYTOTOXIC EFFECTS ON BREAST AND OVARIAN CANCER CELLS
Date
2017-06-05T17:24:30Z
Authors
Greenshields, Anna L.
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Abstract
In women, breast cancer is the most prevalent cancer diagnosis while ovarian
cancer represents the most lethal gynecological neoplasm. The high incidence and
mortality of these cancer types, in addition to the emergence of multi-drug resistant
clones, highlights the need to develop novel therapeutic agents. Artesunate (ART) is a
semi-synthetic derivative of artemisinin, a natural compound derived from the Chinese
herb Artemisia annua L. ART is a potent anti-malarial agent that also possesses anticancer
activity. Since the use of ART as an anti-malarial 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 mechanism(s) underlying its activity. ART exhibited a potent
growth-inhibitory effect on a panel of breast and ovarian cancer cell lines. Anti-cancer
activity was also observed in 3D cultures of both cancer cell types. Oregon Green488 and
propidium iodide (PI) staining of cancer cells revealed that ART strongly inhibited cancer
cell proliferation and, depending on the cell type, arrested cells in the G1 or G2/M phases
of the cell cycle. Arrest in the G2/M phase was dependent on reactive oxygen species
(ROS) production. The anti-proliferative effect of ART was associated with altered
expression of several cell cycle regulatory proteins in both breast and ovarian cancer cell
lines, including cyclin D3, E2F-1, and CDC25C. Annexin-V-FLUOS/PI staining of ARTtreated
cancer cells revealed cytotoxicity against breast and ovarian cancer cell. ARTinduced
cell death was iron- and ROS-dependent. Pre-treatment of cancer cells with a
pan-caspase inhibitor decreased but did not eliminate ART-induced cancer cell death,
suggesting that caspase-dependent apoptosis is involved in ART-mediated cancer cell
killing. ART induced ROS-dependent DNA damage as indicated by the presence of
γH2AX, which implicated the DNA damage pathway in ART-induced cancer cell death.
These data show that ART has a potent anti-proliferative and cytotoxic effect on both
breast and ovarian cancer cells. The cytotoxic activity of ART and its excellent safety
record in malaria patients make ART a worthy candidate for further investigation as a
possible treatment for breast and ovarian cancer.
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Keywords
Artesunate, Ovaries--Cancer, Breast--Cancer, Artemisinin