Isothiouronium salts reduce NRAS expression, induce apoptosis and decrease invasion of melanoma cells
Julia Cisilotto, Misael Ferreira, Fabiola Branco Filippin-Monteiro
1Departamento de Ciencias Farmaceuticas, Universidade Federal de Santa Catarina, 88040-900 Florianopolis, SC, Brazil. tania.pasa@ufsc.br.
Abstract:
Melanoma is a very aggressive type of skin cancer. Mutation in BRAF and NRAS are often found in patients with this disease. Therefore, in recent years the search for new molecules that inhibit these proteins has been intensified. After many years with no new treatments for melanoma, the U.S. Food and Drug Administration (FDA) recently approved vemurafenib. However, many patients have already acquired resistance and have experienced severe side effects. Therefore, this work aims to evaluate a new set of compounds including allylic isothiouronium salts (1, 2 and 3), N-phenyl-substituted analog (4) and isothiosemicarbazide salts (5 and 6) for their potential antimelanoma activity. To this end, viability assay, cell cycle analysis, expression of NRAS and BRAF, as well as migration and invasion assay were performed with different melanoma cell lines. Isothiouronium salts 1-3 presented CC50 (concentration required to reduce the cell number by 50%) in a range of 7-28 μM. Furthermore, salt 1 significantly decreased the expression of NRAS. However, cells incubated with these salts did not disturb the cell cycle phases; instead, an increase in the number of apoptotic cells was observed. Regarding potential antiinvasion effects, both 1 and 2 prevented cell migration as well as cell invasion. Finally, when salts 1 and 2 were associated with vemurafenib, a marked decrease in cell viability was observed when compared to the compounds incubated alone. Briefly, the salts exhibited interesting results, especially 1, which decreased the expression of NRAS, increased apoptotic cells and, when combined with vemurafenib, resulted in a synergistic effect. Therefore, we intend to test compound 1 in pre-clinical studies.
Insights
New isothiouronium salts show promise against melanoma. Compound 1 reduced NRAS expression, increased cell death, and synergized with vemurafenib, warranting further pre-clinical study.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Melanoma is an aggressive skin cancer often driven by BRAF and NRAS mutations.
- Current treatments like vemurafenib face challenges due to resistance and side effects.
- There is an urgent need for novel antimelanoma agents.
Purpose of the Study:
- To evaluate the antimelanoma potential of novel allylic isothiouronium and isothiosemicarbazide salts.
- To investigate their effects on cell viability, cell cycle, apoptosis, and metastasis.
- To assess their synergistic effects when combined with vemurafenib.
Main Methods:
- Viability, cell cycle, apoptosis, migration, and invasion assays were performed on melanoma cell lines.
- NRAS and BRAF expression levels were analyzed.
- Compounds were tested alone and in combination with vemurafenib.
Main Results:
- Isothiouronium salts 1-3 demonstrated significant antimelanoma activity with CC50 values between 7-28 μM.
- Compound 1 reduced NRAS expression and induced apoptosis without affecting cell cycle progression.
- Compounds 1 and 2 inhibited melanoma cell migration and invasion.
- Combination therapy with vemurafenib showed synergistic effects, significantly reducing cell viability.
Conclusions:
- Allylic isothiouronium salts, particularly compound 1, exhibit promising antimelanoma properties.
- Compound 1's ability to reduce NRAS expression and induce apoptosis, along with its synergistic effect with vemurafenib, makes it a strong candidate for pre-clinical development.
- These novel compounds represent a potential new therapeutic strategy for melanoma treatment.
