Susceptibility to cytosine arabinoside (Ara-C)-induced cytotoxicity in human leukemia cell lines.
Cytosine arabinoside (1-beta-d-arabinofuranosylcytosine; Ara-C) is the most important antimetabolite chemotherapeutic drug used for acute leukemia. We examined the difference in susceptibility to Ara-C-induced cell death among a number of typical human leukemia cell lines, NALM-6, MOLT-4, Jurkat, U937 and HL-60. NALM-6, which had a high expression level of p53, a tumor suppressor gene, was most susceptible to Ara-C. U937 and HL-60, with p53-null human leukemia cell lines were little affected by Ara-C. There was not always a correlation between susceptibility and the uptake of Ara-C. The production of reactive oxygen species (ROS) was increased in all leukemia cells. Pifithrin-alpha, a chemical inhibitor of wild-type p53, ameliorated the cytotoxicity of Ara-C in NALM-6 and MOLT-4, but not Jurkat, U937 or HL-60. Our data suggest that the mechanism of Ara-C-induced cell death is a common one, involving an increase in the production of ROS and p53-dependent cell death.
Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Syu-Ichi
S
Kanno
Ayako
A
Higurashi
Yurie
Y
Watanabe
Ai
A
Shouji
Keiko
K
Asou
Masaaki
M
Ishikawa
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D003561:Cytarabine / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016158:Genes, p53; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D003561:Cytarabine