The Key to Unlocking the Chemotherapeutic Potential of PPARγ Ligands: Having the Right Combination

Despite extensive preclinical evidence that peroxisome proliferator-activated receptor (PPAR)gamma activation protects against tumourigenesis, results from a few clinical trials using PPAR gamma ligands as monotherapy show modest success. In spite of this, several groups reported exciting results with therapeutic regimens that combine PPAR gamma ligands with other compounds: chemotherapeutic agents, retinoid x receptor (RXR)alpha agonists, statins, or cell-to-cell signaling molecules in preclinical cancer models and human trials. Here we have compiled an extensive review, consolidating the existing literature, which overwhelmingly supports a beneficial effect of treating with PPAR gamma ligands in combination with existing chemotherapies versus their monotherapy in cancer. There are many examples in which combination therapy resulted in synergistic/additive effects on apoptosis, differentiation, and the ability to reduce cell growth and tumour burden. There are also studies that indicate that PPAR gamma ligand pretreatment overcomes resistance and reduces toxicities. Several mechanisms are explored to explain these protective effects. This paper highlights each of these studies that, collectively, make a very strong case for the use of PPAR gamma ligands in combination with other agents in the treatment and management of several cancers.