| In vitro: |
| Cell Death Dis. 2014 Sep 4;5:e1400. | | Adenanthin targets peroxiredoxin I/II to kill hepatocellular carcinoma cells.[Pubmed: 25188510] | Adenanthin, 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.
METHODS AND RESULTS:
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.
CONCLUSIONS:
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. | | Biochem Pharmacol. 2014 May 15;89(2):210-6. | | Adenanthin targets proteins involved in the regulation of disulphide bonds.[Pubmed: 24630929] | Adenanthin has been recently shown to inhibit the enzymatic activities of peroxiredoxins (Prdx) I and II through its functional α,β-unsaturated ketone group serving as a Michael acceptor. A similar group is found in SK053, a compound recently developed by our group to target the thioredoxin-thioredoxin reductase (Trx-TrxR) system.
METHODS AND RESULTS:
This work provides evidence that next to Prdx I and II Adenanthin targets additional proteins including thioredoxin-thioredoxin reductase system as well as protein disulfide isomerase (PDI) that contain a characteristic structural motif, referred to as a thioredoxin fold. Adenanthin inhibits the activity of Trx-TR system and PDI in vitro in the insulin reduction assay and decreases the activity of Trx in cultured cells. Moreover, we identified Trx-1 as an Adenanthin binding protein in cells incubated with biotinylated Adenanthin as an affinity probe.
CONCLUSIONS:
The results of our studies indicate that Adenanthin is a mechanism-selective, rather than an enzyme-specific inhibitor of enzymes containing readily accessible, nucleophilic cysteines. This observation might be of importance in considering potential therapeutic applications of Adenanthin to include a range of diseases, where aberrant activity of Prdx, Trx-TrxR and PDI is involved in their pathogenesis. |
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