Preclinical Evaluation of Artesunate as an Antineoplastic Agent in Ovarian Cancer Treatment.

Anthony Mcdowell,Kristen S Hill,Yilin Zhang,Fred Ueland,Jill M Kolesar,Justin Gorski,Joseph Robert Mccorkle,Ameen A Salahudeen

doi:10.3390/diagnostics11030395

Anthony Mcdowell, Kristen S Hill + Show 6 more

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https://doi.org/10.3390/diagnostics11030395

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Abstract

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.

Highlights

The American Cancer Society estimates 21,410 new cases of ovarian cancer in the United States in 2021 [1]
Gynecologic Oncology Group (GOG) study 111 first showed improved survival with paclitaxel and cisplatin versus cyclophosphamide and cisplatin [2]. This was followed by GOG 158, which demonstrated the equivalence of carboplatin and paclitaxel compared to cisplatin and paclitaxel with decreased toxicity [3]
To evaluate the antineoplastic activity of artesunate in ovarian cancer, we assessed the dose-dependent effect of artesunate on the viability of three epithelial ovarian cancer cell lines: Caov-3, UWB1.289, and OVCAR-3 using the CellTiter-Glo 2.0 assay

Summary

Introduction

The American Cancer Society estimates 21,410 new cases of ovarian cancer in the United States in 2021 [1]. With a 5-year overall survival of less than 50%, ovarian cancer is the deadliest gynecologic malignancy Despite these grim statistics, there has been little improvement in patient outcomes since the early 2000s. Since 2003, the carboplatin and paclitaxel doublet has been the standard of care for the adjuvant treatment of advanced ovarian cancer. Up to 80% of patients with advanced ovarian cancer who undergo a combination of platinum and taxane-based chemotherapy will develop recurrence. These outcomes demonstrate the need to identify additional therapeutic regimens that can be utilized to better treat patients with ovarian cancer. Artesunate has broad antineoplastic properties but has not been investigated in combination with carboplatin and paclitaxel for ovarian cancer treatment. Conclusions: Artesunate has preclinical activity in ovarian cancer that merits further investigation to treat ovarian cancer

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