Research ArticleCancer

Curaxins: Anticancer Compounds That Simultaneously Suppress NF-κB and Activate p53 by Targeting FACT

Science Translational Medicine  10 Aug 2011:
Vol. 3, Issue 95, pp. 95ra74
DOI: 10.1126/scitranslmed.3002530

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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 Ser392 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.

Footnotes

  • * These authors contributed equally to this work.

  • Present address: Division of Molecular Medicine, Bose Institute, Calcutta University, 700009 India.

  • Present address: Cell and Developmental Biology Program, Vanderbilt University, Nashville, TN 37240, USA.

  • Citation: A. V. Gasparian, C. A. Burkhart, A. A. Purmal, L. Brodsky, M. Pal, M. Saranadasa, D. A. Bosykh, M. Commane, O. A. Guryanova, S. Pal, A. Safina, S. Sviridov, I. E. Koman, J. Veith, A. A. Komar, A. V. Gudkov, K. V. Gurova, Curaxins: Anticancer Compounds that Simultaneously Suppress NF-κB and Activate p53 by Targeting FACT. Sci. Transl. Med. 3, 95ra74 (2011).

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