A novel peroxisome proliferator-activated receptor delta antagonist, SR13904, has anti-proliferative activity in human cancer cells

Abstract

The peroxisome proliferator-activated receptor delta (PPARdelta) is a ligand-activated, nuclear receptor transcription factor that has a documented role in glucose and lipid homeostasis. Recent studies have implicated this nuclear receptor in numerous aspects of oncogenesis. We report herein the characterization of a novel small-molecule (SR13904) that inhibits PPARdelta agonist-induced transactivation and functions as a PPARdelta antagonist. SR13904 also antagonizes PPARgamma transactivation, albeit with much weaker potency. SR13904 displays inhibitory effects on cellular proliferation and survival in several human carcinoma lines, including lung, breast and liver. These inhibitory effects of SR13904 on tumor cells were linked to a G(1)/S cell cycle block and increased apoptosis. Molecular studies show that SR13904 treatment of a lung cancer cell line, A549, results in markedly reduced levels of a number of cell cycle proteins including cyclin A and D, and cyclin dependent kinase (CDK) 2 and 4. The inhibitory effects on CDK2 appear to be transcriptional. Several of these cell cycle-related genes are known to be upregulated by PPARdelta. The antitumor activities of SR13904 suggest that antagonism of PPARdelta-mediated transactivation may inhibit tumorigenesis and that pharmacological inhibition of PPARdelta may be a potential strategy for treatment or prevention of cancer.

Cellular and Pharmacological Selectivity of the Peroxisome Proliferator-Activated Receptor-β/δ Antagonist GSK3787

“…Results from these studies are in contrast to a recent report suggesting that antagonism of PPAR␤/␦ with 10 M SR13904 inhibited cell proliferation of A549 cells (Zaveri et al, 2009). However, data from the present study and recent work by others (Shearer et al, 2010) show that antagonism of PPAR␤/␦ in the same human lung cancer cell line has no effect on cell proliferation at concentrations that specifically antagonize PPAR␤/␦.…”

“…However, data from the present study and recent work by others (Shearer et al, 2010) show that antagonism of PPAR␤/␦ in the same human lung cancer cell line has no effect on cell proliferation at concentrations that specifically antagonize PPAR␤/␦. It is important to note that the study by Zaveri et al (2009) had limitations that preclude definitive conclusions regarding the specificity of the response observed with SR13904 because they did not demonstrate an increase in A549 cell growth by ligand activation of PPAR␤/␦ that was prevented by cotreatment with SR13904. This is a concern because no effect on cell proliferation is found in response to ligand activation of PPAR␤/␦ in A549 cells as shown by the present study and another recent report .…”

“…This is a concern because no effect on cell proliferation is found in response to ligand activation of PPAR␤/␦ in A549 cells as shown by the present study and another recent report . Moreover, Zaveri et al (2009) did not demonstrate specific antagonism of ligand-induced PPAR␤/␦ target gene(s) or altered cell proliferation using knockout or knockdown approaches. This raises the possibility that the observed inhibition of cell proliferation in A549 cells by high concentration SR13904 is due to off target effects rather than antagonism of PPAR␤/␦, in particular because SR13904 was also shown to antagonize PPAR␥ (Zaveri et al, 2009).…”

“…Toward this goal, the recent identification of GSK0660 (Shearer et al, 2008) and SR13904 (Zaveri et al, 2009) as PPAR␤/␦ antagonists was a step in the right direction. Unfortunately, these antagonists have limited application because GSK0660 is not bioavailable, and the bioavailability of SR13904 has not been evaluated (Shearer et al, 2008;Zaveri et al, 2009). In contrast, the recently described PPAR␤/␦ antagonist 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787; Fig.…”

Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618

“…The same research group recently developed the acrylonitrile compound DG172 (6) which exhibited potent PPARβ/δ antagonism and oral bioavailability [21]. As carboxylic acids are canonical agonists of the PPAR receptors, it is notable that also SR13904 (7) [22], reported by Zaveri et al as well as the acid 3a (8) [23], reported by Kasuga et al, exhibited PPARβ/δ antagonism. In 2010, Shearer et al reported the potent PPARβ/δ antagonist GSK3787 (9) [24] which displayed good oral pharmacokinetic properties.…”