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

Despite extensive preclinical evidence that peroxisome proliferator-activated receptor (PPAR) γ activation protects against tumourigenesis, results from a few clinical trials using PPAR γ ligands as monotherapy show modest success. In spite of this, several groups reported exciting results with therapeutic regimens that combine PPAR γ ligands with other compounds: chemotherapeutic agents, retinoid x receptor (RXR) α 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 γ 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 γ 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 γ ligands in combination with other agents in the treatment and management of several cancers.