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Updated: Aug 11, 2025
The Three-Dimensional Human Skin Reconstruct Model: a Tool to Study Normal Skin and Melanoma Progression
Published on: August 3, 2011
Selectively inhibiting malignant melanoma migration and invasion in an engineered skin model using actin-targeting
Ahtasham Raza1, Stuart A Archer2, Jim A Thomas2
1Materials Science & Engineering, University of Sheffield Mappin St Sheffield S1 3JD UK s.macneil@sheffield.ac.uk j.w.haycock@sheffield.ac.uk.
Abstract:
Due to the poor prognosis of metastatic cancers, there is a clinical need for agents with anti-metastatic activity. Here we report on the anti-metastatic effect of a previously reported Ru(ii) complex [{(phen)2Ru}2(tpphz)]4+, 14+, that has recently been shown to disrupt actin fiber assembly. In this study, we investigated the anti-migratory effect of +14+ and a close structural analogue+, 24+, on two highly invasive, metastatic human melanoma cell lines. Laser scanning confocal imaging was used to investigate the structure of actin filament and adhesion molecule vinculin and results show disassembly of central actin filaments and focal adhesions. The effect of both compounds on actin filaments was also found to be reversible. As these results revealed that the complexes were cytostatic and produced a significant inhibitory effect on the migration of both melanoma cell lines but not human dermal fibroblasts their effect on 3D-spheroids and a tissue-engineered living skin model were also investigated. These experiments demonstrated that the compounds inhibited the growth and invasiveness of the melanoma-based spheroidal tumor model and both complexes were found to penetrate the epidermis of the skin tissue model and inhibit the invasion of melanoma cells. Taken together, the cytostatic and antimigratory effects of the complexes results in an antimetastatic effect that totally prevent invasion of malignant melanoma into skin tissue.
Insights
Ruthenium(II) complexes inhibit melanoma cell migration and invasion by disrupting actin filaments and focal adhesions. These compounds show potential as anti-metastatic agents, preventing malignant melanoma spread in skin tissue models.
Area of Science:
- Inorganic Chemistry
- Cancer Biology
- Biophysics
Background:
- Metastatic cancers have a poor prognosis, necessitating novel anti-metastatic agents.
- Ruthenium(II) complexes are being explored for therapeutic applications.
- Previous work showed a Ru(II) complex, 1^4+, disrupts actin fiber assembly.
Purpose of the Study:
- To investigate the anti-migratory and anti-metastatic effects of Ru(II) complexes 1^4+ and 2^4+.
- To elucidate the mechanism of action on melanoma cell cytoskeleton and adhesion.
- To evaluate efficacy in 3D tumor models and a tissue-engineered skin model.
Main Methods:
- Laser scanning confocal microscopy to visualize actin filaments and vinculin.
- Cell migration assays on human melanoma cell lines and dermal fibroblasts.
- 3D spheroid invasion assays.
- Invasion studies using a tissue-engineered living skin model.
Main Results:
- Both Ru(II) complexes disassembled central actin filaments and focal adhesions in melanoma cells.
- The observed effects on actin filaments were reversible.
- Complexes inhibited melanoma cell migration and invasion in a dose-dependent manner.
- No significant effect was observed on human dermal fibroblasts.
- Inhibition of tumor growth and invasiveness in 3D spheroids and skin models.
- Complexes penetrated skin epidermis and prevented melanoma cell invasion.
Conclusions:
- Ruthenium(II) complexes 1^4+ and 2^4+ exhibit significant cytostatic and anti-migratory properties.
- These complexes demonstrate potent anti-metastatic activity by preventing melanoma invasion into skin tissue.
- The findings support the potential of these Ru(II) complexes as therapeutic agents against malignant melanoma metastasis.
