Repurposing Artesunate to Combat Progression and Metastasis via Targeting Circulating Tumor Cells

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Abstract
Objectives: Circulating tumor cells (CTCs) drive metastasis and exhibit resistance to conventional therapies, making them crucial therapeutic targets. Artesunate (AS), a derivative of artemisinin, displays anticancer activity, including inhibition of JunB proto-oncogene (JUNB) and programmed death ligand-1 (PD-L1) and upregulation of Vimentin (VIM), markers related to poor prognosis in CTCs. This study aimed to evaluate the effects of AS on adherent and non-adherent cancer cell lines (breast, lung, colon), the patient-derived colon cancer CTC-MCC-41 line, and CTCs from small-cell lung cancer (SCLC) patients. Methods: AS’s effect was evaluated using TetherChip technology. Cell viability was measured using MTT assay, while immunofluorescence staining and the VyCAP platform were applied to characterize and quantify CTCs. Results: AS significantly reduces viability in all tested cell lines in a time- and concentration-dependent manner, with non-adherent cells showing higher resistance. Notably, CTC-MCC-41 cells are the most sensitive to AS treatment. AS demonstrates stronger cytotoxicity than 5-fluorouracil (5-FU) in most cancer models. In SCLC patient samples, AS reduces total CTC counts (p < 0.001), eliminates aggressive phenotypes such as (CK+/CXCR4+/JUNB–) and (CK+/VIM+/GLU+), and increases apoptotic (M30+) CTCs (p = 0.021). AS additionally impairs structural features like microtentacles, which facilitate CTC reattachment. Conclusions: These findings underscore AS’s ability to target metastasis-competent and anoikis-resistant tumor cells, reducing their viability, invasiveness, and survival mechanisms. AS emerges as a promising candidate for anti-metastatic therapy and warrants further investigation in precision oncology.

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