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Trimidox induces apoptosis via cytochrome c release in NALM-6 human B cell leukaemia cells.

Abstract：

:Trimidox (3,4,5-trihydroxybenzamidoxime) has been shown to reduce the activity of ribonucleotide reductase accompanied by growth inhibition and the differentiation of mammalian cells. Here we examine the induction of apoptosis by trimidox in several human leukaemia cell lines, focusing on the release of cytochrome c and the activation of caspase proteases in the human B cell line NALM-6. Induction of apoptosis by trimidox (300 microM) was detected in NALM-6, HL-60 (premyelocytic leukaemia cells), MOLT-4 (an acute lymphoblastic leukaemia cells), Jurkat (a T-cell leukaemia cells), U937 (expressing many monocyte-like characteristics), and K562 (erythroleukaemia). NALM-6 was most affected by trimidox among leukaemia cells; therefore, we employed NALM-6 cells in the subsequent experiments. The cells showed a time-dependent increase in DNA damage after trimidox (250 microM) treatment. A significant increase in the amount of cytochrome c release was detected after treatment with trimidox. Bcl-2 and Bax protein expressions were not changed by trimidox. Caspase-3 and -9 were activated by incubation with trimidox, whereas caspase-8 was not. Furthermore, trimidox-induced apoptosis was prevented by a broad-spectrum caspase inhibitor, a caspase-3, and a caspase-9 inhibitor, but not by a caspase-8 inhibitor. Inhibition of c-Jun NH2-terminal kinase (JNK) by SP600125 appreciably protected cells from trimidox-induced apoptosis, but no effect inhibition of p38 mitogen-activated protein kinase (MAPK) by SB203580. In contrast, extracellular signal-regulated kinase (ERK) inhibitors U0126 and PD98059 strongly potentiated the apoptotic effect of trimidox. This report shows that the induction of apoptosis by trimidox occurs through a cytochrome c-dependent pathway, which sequentially activates caspase-3 and caspase-9.

journal_name

Basic Clin Pharmacol Toxicol

journal_title

Basic & clinical pharmacology & toxicology

authors

Kanno S,Uwai K,Tomizawa A,Hiura T,Osanai Y,Ujibe M,Takeshita M,Ohtake T,Kimura K,Ishikawa M

doi

10.1111/j.1742-7843.2006.pto_188.x

subject

Has Abstract

pub_date

2006-01-01 00:00:00

pages

44-50

issue

eissn

1742-7835

issn

1742-7843

pii

PTOpto_188

journal_volume

pub_type

杂志文章

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Trimidox induces apoptosis via cytochrome c release in NALM-6 human B cell leukaemia cells.