[The mechanisms of arsenic trioxide-induced apoptosis in hematopoietic malignant cells].
OBJECTIVE
To understand if arsenic trioxide (As2O3) is related to the alteration of mitochondrial transmembrane potentials (delta psi m) and its possible mechanisms.


METHODS
Acute promyelocytic leukemia (APL) cell line NB4, chronic lymphoblastic leukemia (CLL) cell line SKW-3, Burkitt's lymphoma cell line Namalwa and other acute myeloid leukemia cell lines HL-60 and U937 were used as in vitro models. The delta psi m was detected by the double staining of propidium iodide (PI) and Rhodamine 123(Rh123), while apoptosis was confirmed by cell viability, sub-G1 cell content as well as gel electrophoresis of genomic DNA and morphological observation. In addition, cellular content of malondialdehyde (MDA) was detected.


RESULTS
In the cells sensitive to As2O3-induced apoptosis, the delta psi m was disrupted with As2O3 treatment. The disulfide-bond reducing agent dithiothreitol (DTT) significantly blocked As2O3-induced delta psi m collapse and apoptosis. For example, with 1 mumol/L As2O3 treatment for 48 hours, PI- Rh123- cells was increased to (16.0 +/- 2.5)%, and DTT simultaneous treatment reduced PI- Rh123- cells and apoptotic cells to (2.9 +/- 0.2)%, and (1.8 +/- 0.3)%, respectively. On the other hand, As2O3 also significantly induced MDA production in NB4(0.479 +/- 0.044, P < 0.01) and SKW-3 (0.168 +/- 0.018) nmol/L, P < 0.01) cells, whereas the effect could not be blocked by DTT.


CONCLUSIONS
The disruption of the delta psi m is the key event of As2O3-induced apoptosis, and the essential mechanisms may be related to the oxidation of thiols; the reactive oxygen species are involved with apoptosis induced by As2O3, but they are not the main points.
Cai
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X
Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, Shanghai 200025.
Chen
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G
Jia
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P
D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D018922:HL-60 Cells / Q000473:pathology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D010087:Oxides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020298:U937 Cells / Q000473:pathology
D001152:Arsenicals; D010087:Oxides; D000077237:Arsenic Trioxide