Curaxins: anticancer compounds that simultaneously suppress NF-κB and activate p53 by targeting FACT.

Abstract

Effective eradication of cancer requires treatment directed against multiple targets. The p53 and nuclear factor κB (NF-κB) pathways are dysregulated in nearly all tumors, making them attractive targets for therapeutic activation and inhibition, respectively. We have isolated and structurally optimized small molecules, curaxins, that simultaneously activate p53 and inhibit NF-κB without causing detectable genotoxicity. Curaxins demonstrated anticancer activity against all tested human tumor xenografts grown in mice. We report here that the effects of curaxins on p53 and NF-κB, as well as their toxicity to cancer cells, result from "chromatin trapping" of the FACT (facilitates chromatin transcription) complex. This FACT inaccessibility leads to phosphorylation of the p53 Ser(392) by casein kinase 2 and inhibition of NF-κB-dependent transcription, which requires FACT activity at the elongation stage. These results identify FACT as a prospective anticancer target enabling simultaneous modulation of several pathways frequently dysregulated in cancer without induction of DNA damage. Curaxins have the potential to be developed into effective and safe anticancer drugs.

• Authors: Alexander V Gasparian, Catherine A Burkhart, Andrei A Purmal, Leonid Brodsky, Mahadeb Pal, Madhi Saranadasa, Dmitry A Bosykh, Mairead Commane, Olga A Guryanova, Srabani Pal, Alfiya Safina, Sergey Sviridov, Igor E Koman, Jean Veith, Anton A Komar, Andrei V Gudkov, Katerina V Gurova
• Journal: Science translational medicine (Sci Transl Med) Vol. 3 Issue 95 Pg. 95ra74 (Aug 10 2011) ISSN: 1946-6242 [Electronic] United States
• PMID: 21832239 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CBLC137
• Carbazoles
• Chromatin
• DNA-Binding Proteins
• High Mobility Group Proteins
• NF-kappa B
• SSRP1 protein, human
• Transcriptional Elongation Factors
• Tumor Suppressor Protein p53
• Casein Kinase II
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Carbazoles (chemistry, pharmacology)
• Casein Kinase II (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromatin (metabolism)
• Cisplatin (pharmacology)
• DNA Damage
• DNA-Binding Proteins (metabolism)
• High Mobility Group Proteins (metabolism)
• Humans
• Mice
• Models, Biological
• NF-kappa B (antagonists & inhibitors, metabolism)
• Protein Binding (drug effects)
• Transcription, Genetic (drug effects)
• Transcriptional Elongation Factors (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays