Dimeric procyanidin B2 inhibits constitutively active NF-κB in Hodgkin's lymphoma cells independently of the presence of IκB mutations

Gerardo Mackenzie, Ana M. Adamo, Noah P. Decker, Patricia I. Oteiza

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Due to long-term toxicity of current Hodgkin's lymphoma (HL) treatment, the present challenge is to find new therapies that specifically target deregulated signaling cascades, including NF-κB, which are involved in Hodgkin (H) and Reed-Sternberg (RS) cell proliferation and resistance to apoptosis. We previously presented evidence that dimeric procyanidin B2 (B2) can interact with NF-κB proteins inhibiting the binding of NF-κB to DNA. Herein, we investigated if B2, acting at a late event in NF-κB signaling cascade, could be effective in inhibiting NF-κB in H-RS cells with different mechanisms of constitutive NF-κB activation. B2 caused a concentration-dependent inhibition of NF-κB-DNA binding to a similar extent (41-48% inhibition at 25 μM B2) in all the tested H-RS cell lines (L-428, KM-H2, L-540, L-1236 and HDML-2). This was associated with the inhibition of NF-κB-driven gene expression, including cytokines (IL-6, TNFα and RANTES) and anti-apoptotic proteins (Bcl-xL, Bcl-2, XIAP and cFLIP). The finding of similar amounts of RelA and p50 proteins in the nucleus, but decreased NF-κB-DNA binding, even in those H-RS cells characterized by mutations in the inhibitory IκB proteins, supports that B2 acts by preventing the binding of NF-κB to DNA. B2 did not inhibit AP-1 and STAT3 constitutive activation in H-RS cells, indicating that the moderate effects of B2 on cell viability are due to the complex signaling aberrations in HL. Thus, several signaling pathways should be targeted when designing therapeutics for HL. In this regard, the capacity of B2 to inhibit NF-κB could be valuable in a multi-drug approach.

Original languageEnglish (US)
Pages (from-to)1461-1471
Number of pages11
JournalBiochemical Pharmacology
Volume75
Issue number7
DOIs
StatePublished - Apr 1 2008

Keywords

  • Flavanols
  • H-RS cells
  • Hodgkin's lymphoma
  • NF-κB
  • Procyanidin B2

ASJC Scopus subject areas

  • Pharmacology

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