Cantharidin and Its Analogue Norcantharidin Inhibit Metastasis-Inducing Genes S100A4 and MACC1

Colorectal cancer (CRC) is the third most prevalent and second deadliest cancer worldwide. In addition, metastasis directly causes up to 90% of all CRC deaths, highlighting the metastatic burden of the disease. Biomarkers such as S100A4 and MACC1 aid in identifying patients with a high risk of metastasis formation. High expression of S100A4 or MACC1 and to a greater extent the combination of both biomarkers is a predictor for metastasis and poor patient survival in CRC. MACC1 is a tumor-initiating and metastasis-promoting oncogene, whereas S100A4 has not been shown to initiate tumor formation but can, nevertheless, promote malignant tumor growth and metastasis formation. Cantharidin is a natural drug extracted from various blister beetle species, and its demethylated analogue norcantharidin has been shown in several studies to have an anti-cancer and anti-metastatic effect in different cancer entities such as CRC, breast cancer, and lung cancer. The impact of the natural compound cantharidin and norcantharidin on S100A4 and MACC1 gene expression, cancer cell migration, motility, and colony formation in vitro was tested. Here, for the first time, we have demonstrated that cantharidin and norcantharidin are transcriptional inhibitors of S100A4 and MACC1 mRNA expression, protein expression, and motility in CRC cells. Our results clearly indicate that cantharidin and, to a lesser extent, its analogue norcantharidin are promising compounds for efficient anti-metastatic therapy targeting the metastasis-inducing genes S100A4 and MACC1 for personalized medicine for cancer patients.

Automated summary

Colorectal cancer is a prevalent and deadly cancer worldwide, with metastasis being responsible for most deaths. Biomarkers like S100A4 and MACC1 help identify high-risk patients for metastasis. Cantharidin and norcantharidin, natural compounds extracted from blister beetles, have shown anti-cancer and anti-metastatic effects in various cancers. This study demonstrates that cantharidin and norcantharidin inhibit the expression of S100A4 and MACC1, suggesting their potential as promising compounds for personalized anti-metastatic therapy in cancer patients.