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

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.