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

Abstract

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

Loss of PPARγ expression in mammary secretory epithelial cells creates a pro‐breast tumorigenic environment

“…This suggests activation of signaling within other PPARγ‐expressing cells associated with, or near, the mammary gland may contribute to this protective effect, and that activation of normal PPARγ signaling in other PPARγ‐expressing cells common to both strains is chemotherapeutic. This is consistent with reports suggesting that, for some parameters, combination antitumor therapies including PPARγ activators may be beneficial …”

“…This is consistent with reports suggesting that, for some parameters, combination antitumor therapies including PPARg activators may be beneficial. 32 Although no genotypic difference in median mammary tumor volumes was observed for either treatment, cotreatment with ROSI significantly decreased pooled malignant tumor volumes versus those from DMBA only-treated mice. This is consistent with studies showing PPARg activation suppresses carcinogen-induced mammary tumor growth in vivo.…”

Extensive Alternative Splicing of the Repressor Element Silencing Transcription Factor Linked to Cancer

“…PPARγ is implicated in a wide variety of biological processes including adipogenesis, glucose metabolism, inflammation and tumorigenesis, and it is the molecular target of the thiazolidinedione (TZD) class of antidiabetic drugs including pioglitazone and rosiglitazone [51]. It has been shown that TZDs suppress the growth of several cancer lines in vitro and in vivo , and lines of preclinical evidence supports the antineoplstic effects of PPARγ agonists; however, results from clinical trials show modest success [52]. Recently, the use of pioglitazone for type 2 diabetes mellitus is reportedly associated with an increased risk of bladder cancer [53], suggesting a context-dependent, bidirectional effect of PPARγ on tumorigenesis, which is in accordance with its cell-specific effect on E 3 skipping (Fig.5), as well as the notion that both decreased and increased REST activity may contribute to tumorigenesis [18], [19].…”

A specific DNA methylation profile correlates with a high risk of disease progression in stage I classical (Alibert-Bazin type) mycosis fungoides

“…All these findings suggest that a combination of demethylating agents and PPARγ agonists might be a useful therapeutic strategy in high‐risk MF patients. Future drug discoveries could give interesting perspectives in this field …”