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Chiral phenoxyacetic acid analogues inhibit colon cancer cell proliferation acting as PPARγ partial agonists
Lina Sabatino1, Pamela Ziccardi1, Carmen Cerchia2
1Dipartimento di Scienze e Tecnologie, Università del Sannio, via Port'Arsa 11, 82100, Benevento, Italy.
Abstract:
Peroxisome Proliferator-Activated Receptor γ (PPARγ) is an important sensor at the crossroad of diabetes, obesity, immunity and cancer as it regulates adipogenesis, metabolism, inflammation and proliferation. PPARγ exerts its pleiotropic functions upon binding of natural or synthetic ligands. The molecular mechanisms through which PPARγ controls cancer initiation/progression depend on the different mode of binding of distinctive ligands. Here, we analyzed a series of chiral phenoxyacetic acid analogues for their ability to inhibit colorectal cancer (CRC) cells growth by binding PPARγ as partial agonists as assessed in transactivation assays of a PPARG-reporter gene. We further investigated compounds (R,S)-3, (S)-3 and (R,S)-7 because they combine the best antiproliferative activity and a limited transactivation potential and found that they induce cell cycle arrest mainly via upregulation of p21waf1/cip1. Interestingly, they also counteract the β-catenin/TCF pathway by repressing c-Myc and cyclin D1, supporting their antiproliferative effect. Docking experiments provided insight into the binding mode of the most active compound (S)-3, suggesting that its partial agonism could be related to a better stabilization of H3 rather than H11 and H12. In conclusion, we identified a series of PPARγ partial agonists affecting distinct pathways all leading to strong antiproliferative effects. These findings may pave the way for novel therapeutic strategies in CRC.
Insights
New PPARγ partial agonists show significant antiproliferative effects in colorectal cancer (CRC) by targeting key cell cycle and signaling pathways, offering potential new therapeutic strategies.
Area of Science:
- Molecular biology
- Oncology
- Pharmacology
Background:
- Peroxisome Proliferator-Activated Receptor γ (PPARγ) is a key regulator of metabolism, inflammation, and cell proliferation, implicated in diseases including cancer.
- Ligand binding to PPARγ influences its role in cancer initiation and progression.
- Understanding the specific mechanisms of PPARγ modulation is crucial for therapeutic development.
Purpose of the Study:
- To identify and characterize novel PPARγ partial agonists with antiproliferative activity against colorectal cancer (CRC) cells.
- To elucidate the molecular mechanisms underlying the observed anti-cancer effects.
Main Methods:
- Synthesis and screening of chiral phenoxyacetic acid analogues for PPARγ partial agonism using transactivation assays.
- Assessment of antiproliferative effects and cell cycle arrest induction.
- Analysis of key signaling pathways including β-catenin/TCF, c-Myc, and cyclin D1.
- Molecular docking studies to understand ligand-receptor interactions.
Main Results:
- Several chiral phenoxyacetic acid analogues demonstrated partial agonism of PPARγ and significant inhibition of CRC cell growth.
- Compounds (R,S)-3, (S)-3, and (R,S)-7 exhibited potent antiproliferative activity and induced cell cycle arrest, primarily through p21waf1/cip1 upregulation.
- These compounds also repressed the β-catenin/TCF pathway by downregulating c-Myc and cyclin D1.
- Docking experiments suggested that the partial agonism of compound (S)-3 may stem from enhanced stabilization of the H3 region within the PPARγ ligand-binding domain.
Conclusions:
- A series of novel PPARγ partial agonists with potent antiproliferative effects on colorectal cancer cells have been identified.
- These compounds act through multiple pathways, including cell cycle regulation and inhibition of the β-catenin/TCF pathway.
- The findings suggest promising avenues for developing new therapeutic strategies for CRC targeting PPARγ.
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