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Tomatine Displays Antitumor Potential in In Vitro Models of Metastatic Melanoma
Simona Serratì1, Letizia Porcelli1, Stefania Guida2
1Experimental Pharmacology Laboratory, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy.
Abstract:
There is a growing interest in the cytotoxic effects of bioactive glycoalkaloids, such as α-tomatine on tumor cells. Here, for the first time, we determine the antitumor potential of tomatine, a mixture of α-tomatine and dehydrotomatine, in metastatic melanoma (MM) cell lines harboring different BRAF and MC1R variants. We performed cytotoxicity experiments and annexin-V/propidium iodide staining to assess the apoptotic/necrotic status of the cells. ER stress and autophagy markers were revealed by Western Blot, whereas antiangiogenic and vascular-disrupting effects were evaluated through a capillary tube formation assay on matrigel and by ELISA kit for VEGF release determination. Cell invasion was determined by a Boyden chamber matrigel assay. Tomatine reduced 50% of cell viability and induced a concentration-dependent increase of apoptotic cells in the range of 0.5-1 μM in terms of α-tomatine. The extent of apoptosis was more than two-fold higher in V600BRAF-D184H/D184H MC1R cells than in BRAF wild-type cells and V600BRAF-MC1R wild-type cell lines. Additionally, tomatine increased the LC3I/II autophagy marker, p-eIF2α, and p-Erk1/2 levels in BRAF wild-type cells. Notably, tomatine strongly reduced cell invasion and melanoma-dependent angiogenesis by reducing VEGF release and tumor-stimulating effects on capillary tube formation. Collectively, our findings support tomatine as a potential antitumor agent in MM.
Insights
Tomatine, a natural compound, shows significant antitumor effects against metastatic melanoma cells by inducing apoptosis and reducing invasion. It also inhibits angiogenesis, highlighting its potential as a novel cancer therapeutic.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Bioactive glycoalkaloids, like α-tomatine, are increasingly studied for their cytotoxic effects on tumor cells.
- Metastatic melanoma (MM) presents a significant clinical challenge, with genetic variants influencing treatment response.
Purpose of the Study:
- To investigate the antitumor potential of tomatine (α-tomatine and dehydrotomatine) in metastatic melanoma cell lines with varying BRAF and MC1R genotypes.
- To elucidate the mechanisms underlying tomatine's effects, including apoptosis, autophagy, and anti-angiogenesis.
Main Methods:
- Cytotoxicity assays and annexin-V/propidium iodide staining to assess cell death.
- Western Blot analysis for ER stress and autophagy markers (LC3I/II, p-eIF2α, p-Erk1/2).
- Capillary tube formation assay and ELISA for evaluating antiangiogenic effects (VEGF release).
- Boyden chamber matrigel assay to determine cell invasion.
Main Results:
- Tomatine reduced cell viability by 50% and induced apoptosis in a dose-dependent manner (0.5-1 μM α-tomatine).
- Apoptosis was significantly higher (more than two-fold) in V600BRAF-D184H/D184H MC1R cells compared to BRAF wild-type or V600BRAF-MC1R wild-type cells.
- Tomatine increased autophagy markers (LC3I/II) and stress indicators (p-eIF2α, p-Erk1/2) in BRAF wild-type cells.
- Tomatine markedly inhibited cell invasion and melanoma-associated angiogenesis by decreasing VEGF release and capillary tube formation.
Conclusions:
- Tomatine exhibits significant antitumor activity against metastatic melanoma cells, acting through apoptosis induction and inhibition of invasion.
- The compound demonstrates antiangiogenic properties by reducing VEGF levels and disrupting tumor vascularization.
- Tomatine's efficacy varies with genetic background, suggesting potential for targeted therapy in specific melanoma subtypes.
- These findings support tomatine as a promising natural compound for further development as an antitumor agent in metastatic melanoma.
