Potential Benefits of Glitazones for Cancer and Vascular Disease

Glitazones were introduced into clinical use to offer type II diabetic patients an alternative to oral hypoglycaemic agents. Unlike traditional agents based on β-pancreatic overstimulation, glitazones raise peripheral insulin sensitivity allowing the patient to efficiently use his own insulin. Although glitazones are only approved for the treatment of diabetes, their beneficial effects extend to every symptom of the so-called metabolic syndrome: they protect against atherosclerosis, inhibit blood coagulation, decrease hypertension and improve vascular endothelial function. Moreover, glitazones counteract activation of macrophages and brain microglia, attenuate the expression of pro-inflammatory genes, and inhibit various signalling events involved in inflammation. In addition, glitazones are able to induce cell differentiation and apoptosis in several cancer cells, suggesting possible use of these drugs for the treatment of gliomas and other tumors. The molecular basis of such a vast array of glitazone actions is necessarily complex. Glitazone effects were originally attributed to activation of peroxisome proliferator activated receptor-γ (PPARγ). However, several properties of glitazones are unrelated to PPARγ. We review here the emerging actions of glitazones focusing on their antihypertensive and anti-tumoral effects, PPARγ-dependent and -independent, and also emphasizing the contribution of mitochondria and reactive oxygen and nitrogen species to these actions.