L-ascorbic acid represses constitutive activation of NF-kappaB and COX-2 expression in human acute myeloid leukemia, HL-60.

Abstract

There is increasing evidence that L-ascorbic acid (LAA) is selectively toxic to some types of cancer cells at pharmacological concentrations, functioning as a pro-oxidant rather than as an anti-oxidant. However, the molecular mechanisms by which LAA initiates cellular signaling leading to cell death are still unclear. In an effort to gain insight into these mechanisms, the effects of LAA on eukaryotic transcription nuclear factor NF-kappaB and cyclooxygenase-2 (COX-2) expression were investigated. In the present study, LAA suppressed DNA binding activity of NF-kappaB, composed of a p65/p50 heterodimer, through inhibition of degradation of inhibitory kappaB-alpha (IkappaB-alpha) and prevention of nuclear translocation of p65. The inhibitory effect of LAA on NF-kappaB activity was dependent upon glutathione levels in HL-60 cells, as well as generation of H2O2 but not superoxide anion. LAA also downregulated the expression of COX-2, which has a NF-kappaB binding site on its promoter, through repressing NF-kappaB DNA binding activity. Moreover, cotreatment of 1 microM arsenic trioxide (As2O3) with various concentrations of LAA enhanced an LAA-induced repression of NF-kappaB activity and COX-2 expression. In conclusion, our data suggest that LAA exerts its anti-tumor activity through downregulation of NF-kappaB activity and COX-2 expression, and these inhibitory effects can be enhanced by co-treatment with As2O3.

• Authors: Seong-Su Han, Kihyun Kim, Eun-Ryeong Hahm, Sook J Lee, Young-Joon Surh, Hye K Park, Won S Kim, Chul W Jung, Mark H Lee, Keunchil Park, Jung-Hyun Yang, Sung-Soo Yoon, Neil H Riordan, Hugh D Riordan, Bruce F Kimler, Chan H Park, Je-Ho Lee, Seyeon Park
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 93 Issue 2 Pg. 257-70 (Oct 01 2004) ISSN: 0730-2312 [Print] United States
• PMID: 15368354 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2004 Wiley-Liss, Inc.

Chemical References

• Arsenicals
• Isoenzymes
• Membrane Proteins
• NF-kappa B
• Oxides
• Protein Subunits
• Transcription Factor RelA
• Superoxides
• Tosylphenylalanyl Chloromethyl Ketone
• DNA
• Hydrogen Peroxide
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Glutathione
• Ascorbic Acid
• Arsenic Trioxide

Topics

• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Ascorbic Acid (pharmacology)
• Cyclooxygenase 2
• DNA (metabolism)
• Down-Regulation (drug effects)
• Electrophoretic Mobility Shift Assay
• Glutathione (metabolism)
• HL-60 Cells
• Humans
• Hydrogen Peroxide (metabolism)
• Isoenzymes (metabolism)
• Leukemia, Myeloid, Acute (genetics, metabolism)
• Membrane Proteins
• NF-kappa B (antagonists & inhibitors, metabolism)
• Oxides (pharmacology)
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Protein Subunits (genetics, metabolism)
• Superoxides (metabolism)
• Tosylphenylalanyl Chloromethyl Ketone (pharmacology)
• Transcription Factor RelA