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In vitro and in vivo anti-melanoma effects of ciglitazone
Thomas Botton1, Alexandre Puissant, Philippe Bahadoran
1INSERM, U895, Biologie et Pathologie des Cellules Mélanocytaires: de la Pigmentation Cutanée au Mélanome, Nice, France.
Abstract:
Activation of PPARgamma by synthetic ligands, thiazolidinediones, inhibits the proliferation of cancer cells. In this report, focusing our attention on ciglitazone, we show that ciglitazone inhibits melanoma growth by inducing apoptosis and cell-cycle arrest, whereas normal melanocytes are resistant to ciglitazone. In melanoma cells, ciglitazone-induced apoptosis is associated with caspase activations and a loss of mitochondrial membrane potential. Induction of cell-cycle arrest by ciglitazone is associated with changes in expression of key cell-cycle regulators such as p21, cyclin D1, and pRB hypophosphorylation. Cell-cycle arrest occurs at low ciglitazone concentrations and through a PPARgamma-dependent pathway, whereas the induction of apoptosis is caused by higher ciglitazone concentrations and independently of PPARgamma. These results allow an effective molecular dissociation between proapoptotic effects and growth inhibition evoked by ciglitazone in melanoma cells. Finally, we show that in vivo treatment of nude mice by ciglitazone dramatically inhibits human melanoma xenograft development. The data presented suggest that ciglitazone might be a better candidate for clinical trials in melanoma treatment than the thiazolidinediones currently used in the treatment of type 2 diabetes, such as rosiglitazone, which is devoid of a proapoptotic PPARgamma-independent function.
Insights
Ciglitazone effectively inhibits melanoma growth by inducing apoptosis and cell-cycle arrest, while sparing normal cells. This PPARgamma-independent and dependent mechanism offers a promising therapeutic strategy for melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, like thiazolidinediones, inhibit cancer cell proliferation.
- Melanoma is a significant form of skin cancer with a need for effective targeted therapies.
Purpose of the Study:
- To investigate the anti-melanoma effects of ciglitazone, a PPARgamma ligand.
- To elucidate the molecular mechanisms underlying ciglitazone's action in melanoma cells.
- To evaluate ciglitazone's efficacy in vivo for melanoma xenografts.
Main Methods:
- Cell culture of melanoma cells and normal melanocytes.
- Assessment of apoptosis via caspase activation and mitochondrial membrane potential.
- Cell-cycle analysis and Western blotting for cell-cycle regulators (p21, cyclin D1, pRB).
- In vivo studies using human melanoma xenografts in nude mice.
Main Results:
- Ciglitazone inhibited melanoma cell proliferation, induced apoptosis, and caused cell-cycle arrest.
- Apoptosis was linked to caspase activation and loss of mitochondrial potential, occurring at higher ciglitazone concentrations independently of PPARgamma.
- Cell-cycle arrest occurred at lower concentrations via a PPARgamma-dependent pathway.
- Normal melanocytes were resistant to ciglitazone's effects.
- Ciglitazone significantly inhibited melanoma xenograft growth in vivo.
Conclusions:
- Ciglitazone exhibits potent anti-melanoma activity through distinct PPARgamma-dependent and independent pathways.
- The differential effects on cancer cells versus normal cells, and the dual mechanism of action, suggest ciglitazone's potential as a melanoma therapeutic.
- Ciglitazone may be a more suitable candidate for melanoma clinical trials compared to existing diabetes-associated thiazolidinediones.
