Title:Antineoplastic Effects of PPARγ Agonists, with a Special Focus on Thyroid Cancer
Volume: 23
Issue: 7
Author(s): Silvia Martina Ferrari, Gabriele Materazzi, Enke Baldini, Salvatore Ulisse, Paolo Miccoli, Alessandro Antonelli and Poupak Fallahi
Affiliation:
Keywords:
Peroxisome Proliferator-Activated Receptor-γ, thiazolidinediones, PPARγ agonists, antineoplastic effects,
thyroid cancer, differentiated thyroid cancer, anaplastic thyroid cancer.
Abstract: Peroxisome Proliferator-Activated Receptor-γ (PPARγ) 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 PPARγ is overexpressed
in many tumor types, including cancers of breast, lung, pancreas, colon, glioblastoma,
prostate and thyroid differentiated/anaplastic cancers. These data suggest a role of PPARγ in tumor development
and/or progression. PPARγ is emerging as a growth-limiting and differentiation-promoting factor,
and it exerts a tumor suppressor role.
Moreover, naturally-occurring and synthetic PPARγ agonists promote growth inhibition and apoptosis. Thiazolidinediones
(TZDs) are synthetic agonists of PPARγ that were developed to treat type II diabetes. These
compounds also display anticancer effects which appear mainly to be independent of their PPARγ 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. PPARγ 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 PPARγ 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.
