| Autor: |
Zanrè V; Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy., Bellinato F; Section of Dermatology and Venereology, Department of Medicine, University of Verona, Piazzale Stefani 1, 37126 Verona, Italy., Cardile A; Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy., Passarini C; Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy., Di Bella S; Clinical Department of Medical, Surgical and Health Sciences, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy., Menegazzi M; Section of Biochemistry, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy. |
| Abstrakt: |
Melanoma is an aggressive cancer characterized by rapid growth, early metastasis, and poor prognosis, with resistance to current therapies being a significant issue. BRAF mutations drive uncontrolled cell division by activating the MAPK pathway. In this study, A375 and FO-1, BRAF-mutated melanoma cell lines, were treated for 4-5 months with RAF inhibitor dabrafenib or AZ628, leading to drug resistance over time. The resistant cells showed altered molecular signatures, with differences in cell cycle regulation and the propensity of cell death. Dabrafenib-resistant cells maintained high proliferative activity, while AZ628-resistant cells, especially A375 cells, exhibited slow-cycling, and a senescent-like phenotype with high susceptibility to ferroptosis, a form of cell death driven by iron. Antiretroviral drugs doravirine and cabotegravir, known for their effects on human endogenous retroviruses, were tested for their impact on these resistant melanoma cells. Both drugs reduced cell viability and colony formation in resistant cell lines. Doravirine was particularly effective in reactivating apoptosis and reducing cell growth in highly proliferative resistant cells by increasing tumor-suppressor proteins p16 Ink4a and p27 Kip1 . These findings suggest that antiretroviral drugs can influence apoptosis and cell proliferation in RAF-inhibitor-resistant melanoma cells, offering potential therapeutic strategies for overcoming drug resistance. |
