The synthetic epoxyquinoids jesterone dimer and epoxyquinone A monomer induce apoptosis and inhibit REL (human c-Rel) DNA binding in an IκBα-deficient diffuse large B-cell lymphoma cell line

Liang, Mei-Chih; Bardhan, Sujata; Porco, John A.; Gilmore, Thomas D.

doi:10.1016/j.canlet.2005.10.004

« Previous Next »Cancer Letters
Volume 241, Issue 1 , Pages 69-78, 8 September 2006

The synthetic epoxyquinoids jesterone dimer and epoxyquinone A monomer induce apoptosis and inhibit REL (human c-Rel) DNA binding in an IκBα-deficient diffuse large B-cell lymphoma cell line

Mei-Chih Liang
- Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA
Sujata Bardhan
- Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA
- Center for Chemical Methodology and Library Development, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA
John A. Porco Jr.
- Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA
- Center for Chemical Methodology and Library Development, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA
Thomas D. Gilmore
- Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA
- Center for Chemical Methodology and Library Development, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA
- Corresponding author. Address: Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA. Tel.: +1 617 353 5444; fax: +1 617 353 6340.

Received 16 August 2005; accepted 7 October 2005.

Abstract

The NF-κB transcription factor signaling pathway is constitutively active in many human cancers, and inhibition of this pathway can often kill cancer cells by inducing apoptosis. In this study, we show that two synthetic epoxyquinoids, jesterone dimer (JD) and epoxyquinone A monomer (EqM), are equally effective at inhibiting the growth of two human lymphoma cell lines that have constitutively nuclear REL (human c-Rel) DNA-binding complexes, but either express (SUDHL-4 cells) or do not express (RC-K8 cells) the NF-κB inhibitor IκBα. Furthermore, in these cells, both JD and EqM dose-dependently induced apoptosis, inhibited REL DNA-binding activity, and converted REL to a high molecular weight form. In A293 cells, JD and EqM inhibited the DNA-binding activity of overexpressed REL, but not p50. Replacement of Cys-27 with Ser in REL reduced JD- and EqM-mediated inhibition of REL DNA-binding activity. These results suggest that JD and EqM can induce apoptosis in IκBα-deficient lymphoma cells through a mechanism involving direct inhibition of transcription factor REL.

Keywords: NF-kappaB, REL, Jesterone dimer, Epoxyquinone A monomer, Epoxyquinoid, Lymphoma