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

• Published in: Leukemia research Vol. 34; no. 7; pp. 925 - 931
• Main Authors: Biswas, Sabyasachi, Zhao, Xiaobin, Mone, Andrew P, Mo, Xiaokui, Vargo, Melissa, Jarjoura, David, Byrd, John C, Muthusamy, Natarajan
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2010
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Amitrole - pharmacology; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Arsenic trioxide; Arsenicals - pharmacology; Ascorbic acid; Ascorbic Acid - pharmacology; B-Lymphocytes - drug effects; B-Lymphocytes - pathology; Buthionine Sulfoximine - pharmacology; Catalase - antagonists & inhibitors; Catalase - pharmacology; Cell Line, Tumor - drug effects; CLL; Cysteine Proteases - physiology; Cysteine Proteinase Inhibitors - pharmacology; Drug Evaluation, Preclinical; Drug Synergism; Enzyme Activation - drug effects; Glutathione - metabolism; Hematology, Oncology and Palliative Medicine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Neoplasm Proteins - physiology; Oxidants - pharmacology; Oxidative Stress - drug effects; Oxides - pharmacology; Reactive Oxygen Species - metabolism; Arsenic trioxide; CLL; Ascorbic acid
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2010.01.020

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.