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Research Articles: Therapeutics

Curcumin induces caspase-3-dependent apoptotic pathway but inhibits DNA fragmentation factor 40/caspase-activated DNase endonuclease in human Jurkat cells

Ewa Sikora¹, Anna Bielak-mijewska¹, Adriana Magalska¹, Katarzyna Piwocka¹, Grazyna Mosieniak¹, Magdalena Kalinowska³, Piotr Widlak³, Iwona A. Cymerman² and Janusz M. Bujnicki²

¹ Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology; ² Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cellular Biology in Warsaw, Warsaw, Poland; and ³ Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Branch in Gliwice, Gliwice, Poland

Requests for reprints: Ewa Sikora, Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, 3 Pasteura, 02-093 Warsaw, Poland. Phone: 4822-5892436; Fax: 11-48-228225342. E-mail: e.sikora{at}nencki.gov.pl

Abstract

Curcumin is a natural pigment that has been shown to induce cell death in many cancer cells; however, the death mode depends on the cell type and curcumin concentration. Here we show that, in Jurkat cells, 50 µmol/L curcumin severely lowers cell survival and induces initial stage of chromatin condensation. It also induces caspase-3, which is sufficient to cleave DNA fragmentation factor 45 [DFF45/inhibitor of caspase-activated DNase (ICAD)], the inhibitor of DFF40/CAD endonuclease. However, the release of DFF40/CAD from its inhibitor does not lead to oligonucleosomal DNA degradation in curcumin-treated cells. Moreover, curcumin treatment protects cells from UVC-induced oligonucleosomal DNA degradation. In biochemical experiments using recombinant DFF activated with caspase-3, we show that curcumin inhibits plasmid DNA and chromatin degradation although it does not prevent activation of DFF40/CAD endonuclease after its release from the inhibitor. Using DNA-binding assay, we show that curcumin does not disrupt the DNA-DFF40/CAD interaction. Instead, molecular modeling indicates that the inhibitory effect of curcumin on DFF40/CAD activity results from curcumin binding to the active center of DFF40/CAD endonuclease. [Mol Cancer Ther 2006;5(4):927–34]

Grant support: Scholarship from the Postgraduate School of Molecular Medicine at the Medical University of Warsaw (I.A. Cymerman); European Molecular Biology Organization and Howard Hughes Medical Institute Young Investigator Program (J.M. Bujnicki); and Ministry of Science and Information Society and Technologies grant 3P05A10424 (P. Widlak).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Magalska, unpublished data.

Received 9/ 8/05; revised 12/19/05; accepted 2/15/06.

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