Medicine and Health Sciences
We sought to evaluate a novel PPARδ inhibitor and explore whether this compound could synergize with known chemotherapeutic compounds to kill cancer cells in culture. Methods: A novel PPARδ inhibitor compound, Compound 9, was obtained from the College of Pharmacy at Ferris State University for investigation. A cell line with literature-supported PPAR expression, HCT116 (colorectal cancer), was evaluated by Western blot technique to confirm presence and level of expression of PPAR within each line. HeLa cell lines were used as a negative control. Efficacy of Compound 9 to achieve apoptosis in vitro was evaluated using dose response curves with increasing concentrations of inhibitor. Doxorubicin served as the standard chemotherapeutic agent for comparison. Final evaluation included exposure of Compound 9 to a variety of known PPAR subtype agonists and antagonists to determine if further synergy of apoptosis or reversal of PPAR-mediated suppression of downstream targets occurred. Results: Western blot technique confirmed the presence of high level expression of PPARδ in HCT116 cells and undetectable levels of expression in the HeLa cell lines. Dose response curves using concentrations from 0.3 to 50μM of Compound 9 demonstrated apoptotic cell death at concentrations as low as 40-50 μM. Doxorubicin and Compound 9 did not demonstrate appreciable synergy of apoptotic death when combined at concentrations between 0.3-50μM. When combined with a commercially known PPARδ agonist or antagonist, Compound 9 apoptotic death was also not synergized or blocked. Additionally, alpha, beta and gamma agonists and antagonists did not shown potentiation or blocking of cell death, suggesting that Compound 9 functions through a different mechanism at the PPAR receptor. Conclusions: Compound 9 demonstrates initial efficacy at apoptotic cell death of HCT116 cancer cells. However, further investigation into its interaction at the PPARδ receptor and the exact mechanism by which it causes cell death is warranted.
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Hegwood, Emma OMSIV, "Abstract" (2016). MU-COM Research Day. 34.
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