Arsenic trioxide and ascorbic acid demonstrate promising activity against primary human CLL cells in vitro

Leuk Res. 2010 Jul;34(7):925-31. doi: 10.1016/j.leukres.2010.01.020. Epub 2010 Feb 19.

Abstract

The compromised antioxidant defense system in chronic lymphocytic leukemia (CLL) suggested a potential use for reactive oxygen species (ROS) generating arsenic trioxide (ATO) and ascorbic acid. While both ATO and ascorbic acid mediate cytotoxicity in CLL B cells as single agents, the efficacy of ATO is enhanced by ascorbic acid. This effect is dependent on increased ROS accumulation, as pretreatment of B-CLL cells with a glutathione reducing buthionine sulfoximine or catalase inhibiting aminotriazole, enhanced ATO/ascorbic acid-mediated cytotoxicity. Pretreatment with reducing agents such as catalase, or thiol antioxidant, N-acetyl cysteine or GSH also abrogated ATO/ascorbic acid-mediated cytotoxicity. Furthermore, Hu1D10-mediated cell death was enhanced with ATO and ascorbic acid, thus justifying potential combination of ATO/arsenic trioxide therapy with antibodies such as Hu1D10 that also cause accumulation of ROS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Amitrole / pharmacology
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal, Humanized
  • Arsenic Trioxide
  • Arsenicals / pharmacology*
  • Ascorbic Acid / pharmacology*
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / pathology
  • Buthionine Sulfoximine / pharmacology
  • Catalase / antagonists & inhibitors
  • Catalase / pharmacology
  • Cell Line, Tumor / drug effects
  • Cysteine Proteases / physiology
  • Cysteine Proteinase Inhibitors / pharmacology
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Glutathione / metabolism
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Neoplasm Proteins / physiology
  • Oxidants / pharmacology
  • Oxidative Stress / drug effects
  • Oxides / pharmacology*
  • Reactive Oxygen Species / metabolism

Substances

  • Amino Acid Chloromethyl Ketones
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Arsenicals
  • Cysteine Proteinase Inhibitors
  • Neoplasm Proteins
  • Oxidants
  • Oxides
  • Reactive Oxygen Species
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Buthionine Sulfoximine
  • Catalase
  • Cysteine Proteases
  • apolizumab
  • Glutathione
  • Ascorbic Acid
  • Arsenic Trioxide
  • Amitrole