Abstract
Melanoma is the most common cancer in young adults, with a constantly increasing incidence. Metastatic melanoma is a very aggressive cancer with a 5-year survival rate of about 22−25%. This is, in most cases, due to a lack of therapies which are effective on the long term. Hence, it is crucial to find new therapeutic agents to increase patient survival. Toad venoms are a rich source of potentially pharmaceutically active compounds and studies have highlighted their possible effect on cancer cells. We focused on the venoms of two different toad species: Bufo bufo and Rhinella marina. We screened the venom crude extracts, the fractions from crude extracts and isolated biomolecules by studying their antiproliferative properties on melanoma cells aiming to determine the compound or the combination of compounds with the highest antiproliferative effect. Our results indicated strong antiproliferative capacities of toad venoms on melanoma cells. We found that these effects were mainly due to bufadienolides that are cardiotonic steroids potentially acting on the Na+/K+ ATPase pump which is overexpressed in melanoma. Finally, our results indicated that bufalin alone was the most interesting compound among the isolated bufadienolides because it had the highest antiproliferative activity on melanoma cells.
Highlights
Melanoma originates from melanocytes which derivate from pluripotent cells in the neural crest [1].Melanoma is the deadliest form of skin cancer
The main targeted therapies used in metastatic melanoma treatment act on the MAPK signaling pathway, which is mutated in BRAF and NRAS in about, respectively, 50% and 30% of patients with cutaneous melanoma [6,7]
Bufo bufo and Rhinella marina crude extracts on our three parental sensitive melanoma cell lines and on their three resistant counterparts (Figure 1). These results indicate a similar decrease in cell viability for both extracts in all cell lines excepted in the case of MM161-R which is NRAS mutated and has developed an acquired resistance to pimasertib
Summary
Melanoma is the deadliest form of skin cancer. The main targeted therapies used in metastatic melanoma treatment act on the MAPK signaling pathway, which is mutated in BRAF and NRAS in about, respectively, 50% and 30% of patients with cutaneous melanoma [6,7]. Another important target for these types of therapy is the tyrosine kinase receptor cKIT which is mutated in about 20% of patients with mucosal melanoma [8]. Inhibition of the MAPK pathway shows initially good response, but the large majority of metastatic melanoma patients treated with targeted therapies develop resistances within weeks or months following the onset of treatment [9]
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