Atranorin Triggers Intrinsic and Extrinsic Apoptosis and Suppresses Migration in Human Melanoma Cells

Malignant melanoma is a highly aggressive skin malignancy characterised by metastatic properties and resistance to conventional therapies. This indicates a necessity to explore novel, efficacious treatment modalities. Atranorin, a secondary metabolite derived from lichen, has demonstrated a diverse range of bioactivities. However, the antineoplastic mechanisms of atranorin in melanoma remain underexplored.

Human melanoma cancer cell lines (A-375, G-361, and MDA-MB-435) and normal human melanocytes were treated with various concentrations of atranorin. Cell viability and proliferation were evaluated by MTT assay, apoptosis was assessed using Annexin V-FITC/PI flow cytometry, and cell cycle distribution was determined by PI staining and flow cytometry. Gene expression of apoptosis-related markers was quantified by qRT-PCR, and protein levels were analyzed by western blot. Cell migration was evaluated by the wound healing assay.

Atranorin demonstrated selective toxicity in human melanoma cancer cells, exhibiting minimal effect on normal human melanocytes. In a study on human malignant melanoma A-375 cells, it was found that atranorin, at an IC50 concentration of 12 μM, significantly increased the number of apoptotic cells by approximately 11-fold. Furthermore, the results of the study indicated that atranorin induced G1 phase arrest and inhibited migratory capacity by around 60%. Molecular profiling revealed the upregulation of the intrinsic (APAF1, BAX, and CASP9) and extrinsic (FAS, FADD, and CASP10) apoptotic pathways, and the downregulation of the anti-apoptotic genes BCL2, MCL1, and BIRC5. In line with these observations, protein analyses revealed increased levels of cleaved caspase-3, caspase-9, and PARP, thereby providing evidence for the activation of apoptotic cascades.

In this study, the therapeutic effect of atranorin was comprehensively evaluated for the first time on A-375 melanoma cells, and it was highlighted as a natural compound with strong anti-cancer potential.

This study is the first to demonstrate the potent anti-melanoma effect of atranorin. This demonstrates the natural compounds' effects on cell proliferation, cell cycle progression, and the suppression of metastasis. These findings emphasize the potential of atranorin as a novel natural compound for use in adjunctive or targeted melanoma therapy, and highlight the need for further preclinical and clinical evaluation.