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Antimelanoma effect of manool in 2D cell cultures and reconstructed human skin models
Heloiza D Nicolella1, Arthur B Ribeiro1, Carla Carolina Munari2
1University of Franca, Franca, São Paulo, Brazil.
Abstract:
Melanoma is the most aggressive and lethal type of skin cancer, characterized by therapeutic resistance. In this context, the present study aimed to investigate the cytotoxic potential of manool, a diterpene from Salvia officinalis L., in human (A375) and murine (B16F10) melanoma cell lines. The analysis of cytotoxicity using the XTT assay showed the lowest IC50 after 48 h of treatment with the manool, being 17.6 and 18.2 µg/ml for A375 and B16F10, respectively. A selective antiproliferative effect of manool was observed on the A375 cells based on the colony formation assay, showing an IC50 equivalent to 5.6 µg/ml. The manool treatments led to 43.5% inhibition of the A375 cell migration at a concentration of 5.0 µg/ml. However, it did not affect cell migration in the B16F10 cells. Cell cycle analysis revealed that the manool interfered in the cell cycle of the A375 cells, blocking the G2/M phase. No changes in the cell cycle were observed in the B16F10 cells. Interestingly, manool did not induce apoptosis in the A375 cells, but apoptosis was observed after treatment of the B16F10 cells. Additionally, manool showed an antimelanoma effect in a reconstructed human skin model. Furthermore, in silico studies, showed that manool is stabilized in the active sites of the tubulin dimer with comparable energy concerning taxol, indicating that both structures can inhibit the proliferation of cancer cells. Altogether, it is concluded that manool, through the modulation of the cell cycle, presents a selective antiproliferative activity and a potential antimelanoma effect.
Insights
Manool, a diterpene from Salvia officinalis, selectively inhibits human melanoma cell proliferation by blocking the G2/M phase. This natural compound shows antimelanoma potential, warranting further investigation for therapeutic applications.
Area of Science:
- Pharmacology
- Natural Products Chemistry
- Oncology
Background:
- Melanoma is an aggressive skin cancer with limited treatment options.
- Therapeutic resistance is a significant challenge in melanoma treatment.
- Natural compounds are a promising source for novel anticancer agents.
Purpose of the Study:
- To investigate the cytotoxic and antiproliferative potential of manool, a diterpene from Salvia officinalis L., against human (A375) and murine (B16F10) melanoma cell lines.
- To elucidate the mechanism of action of manool in melanoma cells.
- To evaluate the antimelanoma effect of manool in a reconstructed human skin model.
Main Methods:
- Cytotoxicity was assessed using the XTT assay.
- Antiproliferative effects were evaluated by colony formation assay.
- Cell migration was measured using a wound healing assay.
- Cell cycle progression was analyzed by flow cytometry.
- Apoptosis was detected using specific assays.
- In silico studies were performed to predict the mechanism of action.
Main Results:
- Manool exhibited cytotoxic effects against both A375 and B16F10 cell lines with IC50 values of 17.6 and 18.2 µg/ml, respectively.
- Manool demonstrated selective antiproliferative activity against A375 cells (IC50 = 5.6 µg/ml) and inhibited their migration by 43.5%.
- Manool induced G2/M phase cell cycle arrest in A375 cells and apoptosis in B16F10 cells.
- In silico analysis suggested manool stabilizes tubulin, similar to taxol, indicating a potential mechanism for inhibiting cancer cell proliferation.
- Manool showed an antimelanoma effect in a reconstructed human skin model.
Conclusions:
- Manool possesses selective antiproliferative and antimigratory effects on human melanoma cells.
- Manool modulates the cell cycle, specifically arresting A375 cells in the G2/M phase.
- Manool exhibits potential as an antimelanoma agent, with its mechanism possibly involving tubulin interaction.
