Arsenic trioxide and ascorbic acid demonstrate promising activity against primary human CLL cells in vitro.
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.
Biswas
Sabyasachi
S
Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
Zhao
Xiaobin
X
Mone
Andrew P
AP
Mo
Xiaokui
X
Vargo
Melissa
M
Jarjoura
David
D
Byrd
John C
JC
Muthusamy
Natarajan
N
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000640:Amitrole / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002374:Catalase / Q000037:antagonists & inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D057056:Cysteine Proteases / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D009363:Neoplasm Proteins / Q000502:physiology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001152:Arsenicals; D015853:Cysteine Proteinase Inhibitors; D009363:Neoplasm Proteins; D016877:Oxidants; D010087:Oxides; D017382:Reactive Oxygen Species; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019328:Buthionine Sulfoximine; D002374:Catalase; D057056:Cysteine Proteases; C448699:apolizumab; D005978:Glutathione; D001205:Ascorbic Acid; D000077237:Arsenic Trioxide; D000640:Amitrole