J Natl Cancer I t 1999 May 5;91(9):772-8
Comment in: J Natl Cancer I t. 1999 May 5;91(9):743-5
Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentratio .
Zhu XH, Shen YL, Jing YK, Cai X, Jia PM, Huang Y, Tang W, Shi GY, Sun YP, Dai J, Wang ZY, Chen SJ, Zhang TD, Waxman S, Chen Z, Chen GQ.
Shanghai I titute of Hematology, Rui-Jin Ho ital, Shanghai Second Medical University, People\'s Republic of China.
BACKGROUND: Arsenic trioxide (As2O3) can induce clinical remi ion in patients with acute promyelocytic leukemia via induction of differentiation and programmed cell death (apoptosis). We investigated the effects of As2O3 on a panel of malignant lymphocytes to determine whether growth-inhibitory and apoptotic effects of As2O3 can be o erved in these cells at clinically achievable concentratio . METHODS: Eight malignant lymphocytic cell lines and primary cultures of lymphocytic leukemia and lymphoma cells were treated with As2O3, with or without dithiothreitol (DTT) or buthionine sulfoximine ( O) (an inhibitor of glutathione synthesis). Apoptosis was a e ed by cell morphology, flow cytometry, a exin V protein level, and terminal deoxynucleotidyl tra ferase labeling of DNA fragments. Cellular proliferation was determined by 5-bromo-2\'-deoxyuridine incorporation into DNA and flow cytometry and by use of a mitotic arrest a ay. Mitochondrial tra membrane potential (delta i(m)) was measured by mea of rhodamine 123 staining and flow cytometry. Protein expre ion was a e ed by western blot analysis or immunofluorescence. RESULTS: Therapeutic concentratio of As2O3 (1-2 microM) had dual effects on malignant lymphocytes: 1) inhibition of growth through adenosine tripho hate (ATP) depletion and prolongation of cell cycle time and 2) induction of apoptosis. As2O3-induced apoptosis was preceded by delta i(m) colla e. DTT antagonized and O enhanced As2O3-induced ATP depletion, delta i(m) colla e, and apoptosis. Ca ase-3 activation, usually resulting from delta i(m) colla e, was not always a ociated with As2O3-induced apoptosis. As2O3 induced PML (promyelocytic leukemia) protein degradation but did not modulate expre ion of cell cycle-related protei , including c-myc, retinoblastoma protein, cyclin-dependent kinase 4, cyclin D1, and p53, or expre ion of differentiation-related antige . CONCLUSIO : Su tantial growth inhibition and apoptosis without evidence of differentiation were induced in most malignant lymphocytic cells treated with 1-2 microM As2O3. As2O3 may prove useful in the treatment of malignant lymphoproliferative disorders.
Blood 1999 Jan 1;93(1):268-77
Malignant cells can be se itized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system.
Dai J, Wei erg RS, Waxman S, Jing Y.
Rochelle Belfer Chemotherapy Foundation Laboratory, the Divis