Antineoplastic Effects of PPAR gamma Agonists, with a Special Focus on Thyroid Cancer

作者：Ferrari Silvia Martina; Materazzi Gabriele; Baldini Enke; Ulisse Salvatore; Miccoli Paolo; Antonelli Alessandro^*; Fallahi Poupak

来源：Current Medicinal Chemistry, 2016, 23(7): 636-649.

DOI：10.2174/0929867323666160203114607

• Peroxisome Proliferator-Activated Receptor-gamma
• thiazolidinediones
• PPAR gamma agonists
• antineoplastic effects
• thyroid cancer
• differentiated thyroid cancer
• anaplastic thyroid cancer

Peroxisome Proliferator-Activated Receptor-gamma (PPAR gamma) is a ligand-activated nuclear hormone receptor that functions as transcription factor and plays an important role in lipid metabolism and insulin sensitization. Recent studies have shown that PPAR gamma is over-expressed in many tumor types, including cancers of breast, lung, pancreas, colon, glioblastoma, prostate and thyroid differentiated/anaplastic cancers. These data suggest a role of PPAR gamma in tumor development and/or progression. PPAR gamma is emerging as a growth-limiting and differentiation-promoting factor, and it exerts a tumor suppressor role.
Moreover, naturally-occurring and synthetic PPAR gamma agonists promote growth inhibition and apoptosis. Thiazolidinediones (TZDs) are synthetic agonists of PPAR gamma that were developed to treat type II diabetes. These compounds also display anticancer effects which appear mainly to be independent of their PPAR gamma agonist activity. Various preclinical and clinical studies strongly suggest a role for TZDs both alone and in combination with existing chemotherapeutic agents, for the treatment of cancer.
Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells, targeting pathways capable of re-activating blocked terminal differentiation programs. PPAR gamma agonists have been shown to induce differentiation in solid tumors such as thyroid differentiated/anaplastic cancers and sarcomas.
However, emerging data suggest that chronic use of TZDs is associated with increased risk of adverse cardiovascular events. The exploration of newer PPAR gamma agonists can help in unveiling the underlying mechanisms of these drugs, providing new molecules that are able to treat cancer, without increasing the cardiovascular risk of neoplastic patients.

• 出版日期2016