Melanoma has shown upward trend in incidence and mortality over the last decades. Since the efficacy of conventional therapies is severely limited due to the metastasis of melanoma cells, developing innovative approaches with enhanced specificity is paramount in impeding melanoma progression. Urolithin A (UA) and urolithin B (UB), ellagic acid derivatives with known pharmaceutical benefits, have not been studied for their effects on melanoma metastasis. This study aims to fill that gap by investigating the potential of UA and UB to inhibit the metastatic behavior of melanoma cells. Urolithins were synthesized, and B16F10 cells were treated and evaluated for migration, invasion, adhesion, matrix metalloproteinase (MMP) activity and EMT-associated gene expression. Additionally, interactome mapping was performed, and molecular docking and dynamics simulations were conducted to investigate the interaction between urolithins and MMPs. Obtained findings indicated that UA and UB significantly (p < 0.001) altered the migration, invasion and adhesion abilities of B16F10 cells. Moreover, significant (p < 0.01) reduction in MMP2 and MMP9 activity and significant (p < 0.05) alterations in CDH2 and CTNNB1 expression were detected upon treatment with UA. Computational analyses highlighted MMP9 as a significant pathogenic molecule associated with metastatic melanoma. Results of molecular docking and dynamics simulations revealed favorable and stable interactions of UA and UB with the active sites of MMP2 and MMP9. In conclusion, findings of the present research indicated anti-metastatic effects of UA and UB on melanoma cells for the first time, and introduce urolithins as promising candidates for the development of novel therapeutic strategies against melanoma.

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