Interruption of the Warburg effect - the observation that un-stimulated macrophages reprogram their core metabolism from oxidative phosphorylation toward aerobic glycolysis to become pro-inflammatory M1 macrophages upon stimulation - is an emerging strategy for the treatment of cancer and anti-inflammatory diseases such as rheumatoid arthritis. We studied this process with view to the discovery of novel therapeutics, and found that tylophorine-based compounds targeted a ribonucleoprotein complex containing caprin-1 and mRNAs of c-Myc and HIF-1alpha in LPS/IFN-gamma stimulated Raw264.7 cells, diminished the protein levels of c-Myc and HIF-1alpha, and consequently downregulated their targeted genes that are associated with the Warburg effect, as well as the pro-inflammatory iNOS and COX2. The tylophorine-based compound DBQ 33b significantly meliorated the severity and incidence of type II collagen-monoclonal antibody-induced rheumatoid arthritis and diminished gene expressions of c-Myc, HIF-1alpha, iNOS, COX2, TNFalpha, and IL-17A in vivo. Moreover, pharmacological inhibition of either c-Myc or HIF-1alpha exhibited similar effects as the tylophorine-based compound DBQ 33b, even though inhibition of c-Myc reversed the induction of iNOS and COX2 in LPS/IFN-gamma stimulated Raw264.7 cells to a lesser degree. Therefore, simultaneous inhibition of both c-Myc and HIF-1alpha is efficacious for anti-inflammation in vitro and in vivo and merits further study.
Date:
2020-02
Relation:
Pharmacological Research. 2020 Feb;152:Article number 104581.
