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Thiazolidinediones: anti-diabetic drugs to treat cancer? Thiazolidinediones (TZDs) are potent insulin sensitizers used to prevent and treat type 2 diabetes [1]. Widely-used in the early 2000’, pharmacological treatments with these compounds have been drastically reduced due to adverse effects, like weight gain, hepatotoxicity, and congestive heart failure [1, 2]. Nevertheless, two members of this family of compounds, rosiglitazone (Avandia) and pioglitazone (Actos), are still approved for the treatment of type 2 diabetes in selected patients and under restricted conditions. Besides treatment of diabetes, TZDs have been proposed as a therapeutic option for cancer. This was initially based on the observation that the nuclear receptor PPARγ -the best characterized molecular target of TZDsexhibits anti-cancer properties. PPARγ is involved in the regulation of several conditions that are key for controlling tumor growth, like cell proliferation, cell survival, cell differentiation, and inflammation [2, 3]. Moreover, genetic evidence shows that loss of PPARγ function predisposes to colon, breast, ovary and skin cancers [4]. Finally numerous studies have reported antitumoral effects of PPARγ activation both in vitro and in in vivo mouse models, possibly also in humans [4]. Despite anti-cancer properties reported in many cancer cell types, clinical trials involving TZDs and activation of PPARγ, which were performed over the past 15 years have been disappointing, showing little therapeutic efficacy [2]. Undesirable pro-tumorigenic actions of rosiglitazone in metastatic human melanoma cells. Skin melanoma, an aggressive malignant neoplasm of melanocytes, is the most dangerous form of skin cancer. Although it represents only 4% of all skin cancers, it is currently responsible for 80% of skin cancer-related deaths. Cancer research has taught us that melanoma require multiple therapeutic approaches. The search for treatments against melanoma is therefore still active, despite the recent breakthrough of immunoand molecularly targeted therapies [5]. Several studies conducted over the past 20 years supported the use of TZDs and of PPARγ activation as a therapeutic option to treat melanoma [6]. However, these studies showed anti-cancer effects on the malignant cells (Figure 1), while they neglected the role played by nonmalignant cells of a tumor microenvironment. Recently, Editorial