BACKGROUND: Ovarian cancer is the deadliest gynecologic malignancy despite current first-line treatment with a platinum and taxane doublet. Artesunate has broad antineoplastic properties but has not been investigated in combination with carboplatin and paclitaxel for ovarian cancer treatment.
METHODS: Standard cell culture technique with commercially available ovarian cancer cell lines were utilized in cell viability, DNA damage, and cell cycle progression assays to qualify and quantify artesunate treatment effects. Additionally, the sequence of administering artesunate in combination with paclitaxel and carboplatin was determined. The activity of artesunate was also assessed in 3D organoid models of primary ovarian cancer and RNAseq analysis was utilized to identify genes and the associated genetic pathways that were differentially regulated in artesunate resistant organoid models compared to organoids that were sensitive to artesunate.
RESULTS: Artesunate treatment reduces cell viability in 2D and 3D ovarian cancer cell models. Clinically relevant concentrations of artesunate induce G1 arrest, but do not induce DNA damage. Pathways related to cell cycle progression, specifically G1/S transition, are upregulated in ovarian organoid models that are innately more resistant to artesunate compared to more sensitive models. Depending on the sequence of administration, the addition of artesunate to carboplatin and paclitaxel improves their effectiveness.
CONCLUSIONS: Artesunate has preclinical activity in ovarian cancer that merits further investigation to treat ovarian cancer.
Digital Object Identifier (DOI)
This research was partially funded by the National Cancer Institute, grant number T32 CA160003. The Biospecimen Procurement and Translational Pathology Shared Resource Facility is sup-ported by NCI Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center.
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to HIPPA.
The following are available online at https://www.mdpi.com/2075-4418/11/3/395/s1, Table S1: Significantly differentially expressed genes between the more resistant (1226 and 1254) and sensitive (2238, 2326, 1236, 1267) organoid models; Figure S1: Representative flow cytometry histograms of cell cycle analysis for Caov-3 cells treated for 24hr or 48hr with DMSO control or artesunate; Figure S2: Representative flow cytometry histograms of cell cycle analysis for UWB1 cells treated for 24hr or 48hr with DMSO control or artesunate. They are also available for download as the additional file listed the end of this record.
McDowell, Anthony Jr.; Hill, Kristen S.; McCorkle, Joseph Robert; Gorski, Justin W.; Zhang, Yilin; Salahudeen, Ameen A.; Ueland, Frederick R.; and Kolesar, Jill M., "Preclinical Evaluation of Artesunate as an Antineoplastic Agent in Ovarian Cancer Treatment" (2021). Obstetrics and Gynecology Faculty Publications. 31.