Adenanthin targets peroxiredoxin I/II to kill hepatocellular carcinoma cells

Abstract

Adenanthin, a natural diterpenoid isolated from the leaves of Isodon adenanthus, has recently been reported to induce leukemic cell differentiation by targeting peroxiredoxins (Prx) I and II. On the other hand, increasing lines of evidence propose that these Prx proteins would become potential targets to screen drugs for the prevention and treatment of solid tumors. Therefore, it is of significance to explore the potential activities of adenanthin on solid tumor cells. Here, we demonstrate that Prx I protein is essential for the survival of hepatocellular carcinoma (HCC) cells, and adenanthin can kill these malignant liver cells in vitro and xenografts. We also show that the cell death-inducing activity of adenanthin on HCC cells is mediated by the increased reactive oxygen species (ROS) levels. Furthermore, the silencing of Prx I or Prx II significantly enhances the cytotoxic activity of adenanthin on HCC, whereas the ectopic expression of Prx I and Prx II but not their mutants of adenanthin-bound cysteines can rescue adenanthin-induced cytotoxicity in Prxs-silenced HCC cells. Taken together, our results propose that adenanthin targets Prx I/II to kill HCC cells and its therapeutic significance warrants to be further explored in HCC patients.

Histone acetyltransferase KAT8 is essential for mouse oocyte development by regulating ROS levels

“…For example, in the spleen of Prdx1 knockout mice, Gpx1 expression increases more than 2-fold (Rani et al, 2012). Silencing of Prdx2 alone in hepatocellular carcinoma cells has no effect on cell survival, whereas simultaneous silencing of Prdx1 and Prdx2 promotes cell death (Hou et al, 2014). These studies indicate synergetic effects on cells of Gpx and Prdx factors, and suggest that the simultaneous reduction of Prdx1, Prdx2, Gpx1 and Gpx4 could be the reason for excessive apoptosis in Kat8 Gdf9 cKO oocytes.…”

Interaction of adenanthin with glutathione and thiol enzymes: Selectivity for thioredoxin reductase and inhibition of peroxiredoxin recycling

“…Other electrophiles [27,29,30] also induce apoptotic cell death in association with thioredoxin reductase inhibition, and it seems likely that this mechanism contributed to the loss of cell viability caused by adenanthin. Likewise, other observed effects of adenanthin (or 15Ͳoxospiramilactone) on cell differentiation and tumor growth in APL [1], dampening immune responses and altering NFNB signaling [2] or Wnt/ɴͲcatenin signaling [38], or promoting cell death in hepatocarcinoma cells [39] may involve the thioredoxin and GSH redox systems. There is considerable interest in thioredoxin reductase as a target for anticancer therapy [37], as it promotes tumor growth, is upregulated in various cancers [36, 40Ͳ43], and is associated with drug resistance.…”

Cisplatin induces HepG2 cell cycle arrest through targeting specific long noncoding RNAs and the p53 signaling pathway

“…Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality in the world, and the five-year survival rate is lower than 5% (1). It has an unfavorable prognosis due to its spread, metastases and high rate of recurrence (2).…”