Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria

Genini, Davide; Adachi, Souichi; Qi, Chao; Rose, David W.; Carrera, Carlos J.; Cottam, Howard B.; Carson, Dennis A.; Leoni, Lorenzo M.

doi:10.1182/blood.v96.10.3537.h8003537_3537_3543

Cited by 105 publications

(93 citation statements)

References 33 publications

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“…Other polyhydroxy-substituted benzohydroxamic acid derivatives, amidox and didox, which also inhibit ribonucleotide reductase in leukaemia cells (Tihan et al 1991), induce apoptosis via the activation of caspases (Grusch et al 2001). Chlorodeoxyadenosin, an ribonucleotide reductase inhibitor, was also found to induce DNA damage, mitochondrial dysfunction, release of cytochrome c into the cytosol, and activation of the caspase pathway (Genini et al 2000). These findings were supported by our experiment results.…”

Section: Discussionsupporting

confidence: 83%

Trimidox Induces Apoptosis via Cytochrome c Release in NALM‐6 Human B Cell Leukaemia Cells

Kanno

Uwai

Tomizawa

et al. 2006

Basic Clin Pharma Tox

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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 mM) 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 mM) 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, trimidoxinduced 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 NH 2 -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.

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Section: Discussionsupporting

confidence: 83%

Trimidox Induces Apoptosis via Cytochrome c Release in NALM‐6 Human B Cell Leukaemia Cells

Kanno

Uwai

Tomizawa

et al. 2006

Basic Clin Pharma Tox

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“…Incorporation of F-AraA-TP or CdA-TP into DNA by the repair mechanisms leads to the progressive accumulation of DNA single-strand breaks eventually responsible for apoptosis by both p53-dependent and p53-independent pathways (Sandoval et al, 1996). Another consequence of these treatments is the direct activation of the caspase-9 and caspase-3 pathways by F-AraA-TP and CdA-TP, which are nucleotide activators of Apaf-1 (Genini et al, 2000). Moreover, F-AraA and CdA also alter gene transcription, resulting in depletion of proteins required for cell survival.…”

Section: Deoxyribonucleoside Analoguesmentioning

confidence: 99%

Substrate specificity and phosphorylation of antiviral and anticancer nucleoside analogues by human deoxyribonucleoside kinases and ribonucleoside kinases

Rompay

Johansson

Karlsson

2003

Pharmacology & Therapeutics

135

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Structural analogues of nucleosides, nucleoside analogues (NA), are used in the treatment of cancer and viral infections. Antiviral NAs inhibit replication of the viral genome, whereas anticancer NAs inhibit cellular DNA replication and repair. NAs are inactive prodrugs that are dependent on intracellular phosphorylation to their pharmacologically active triphosphate form. The deoxyribonucleoside kinases (dNK) and ribonucleoside kinases (rNK) catalyze the first phosphorylation step, converting deoxyribonucleosides and ribonucleosides to their corresponding monophosphate form. The dNKs have been studied intensively, whereas the rNKs have not been as thoroughly investigated. This overview is focused on the substrate specificity, tissue distribution, and subcellular location of the mammalian dNKs and rNKs and their role in the activation of NAs.

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“…In these respects, and in contrast to previous studies, the present study investigated the mechanism of CAFdA resistance intensively and extensively. (10)(11)(12)(13)(14) The resistant variants developed here exhibited cross-resistance against similar nucleoside analogs ( Table 1). Because the activation pathway is basically the same, (30) such crossresistance may be caused by the decrease in transport capacity and the reduced dCK.…”

Section: Discussionmentioning

confidence: 89%

“…CAFdATP is incorporated into DNA, thereby terminating DNA elongation and eventually inducing apoptosis. (12)(13)(14)(15)(16)(17) CAFdA also induces apoptosis via direct mitochondrial damage. (13) Pharmacological understanding of action of CAFdA is crucial to its optimal administration.…”

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confidence: 99%

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Novel leukemic cell lines resistant to clofarabine by mechanisms of decreased active metabolite and increased antiapoptosis

et al. 2013

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Clofarabine (CAFdA) is incorporated into leukemic cells by human equilibrative nucleoside transporters (hENT) 1 and 2 and human concentrative nucleoside transporter (hCNT) 3. CAFdA is then phosphorylated to the active metabolite CAFdA triphosphate (CAFdATP) by deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK). Two novel CAFdA‐resistant variants were established and their mechanism of resistance was elucidated. The two variants (HL/CAFdA20, HL/CAFdA80) were 20‐fold and 80‐fold more CAFdA‐resistant than HL‐60, respectively. mRNA levels of hENT1, hENT2 and hCNT3 were 53.9, 41.8 and 17.7% in HL/CAFdA20, and 30.8, 13.9 and 7.9% in HL/CAFdA80, respectively, compared with HL‐60. Thus, the total nucleoside transport capacity of CAFdA was reduced in both variants. dCK protein levels were 1/2 in HL/CAFdA20 and 1/8 in HL/CAFdA80 of that of HL‐60. dGK protein levels were 1/2 and 1/3, respectively. CAFdATP production after 4‐h incubation with 10 μM CAFdA was 20 pmol/107cells in HL/CAFdA20 and 3 pmol/107cells in HL/CAFdA80 compared with 63 pmol/107cells in HL‐60. The decreased CAFdATP production attenuated drug incorporation into both mitochondrial and nuclear DNA. In addition, the two variants were resistant to CAFdA‐induced apoptosis due to Bcl2 overexpression and decreased Bim. A Bcl2 inhibitor, ABT737, acted synergistically with CAFdA to inhibit the growth with combination index values of 0.27 in HL/CAFdA20 and 0.23 in HL/CAFdA80, compared with 0.65 in HL‐60. Thus, the mechanism of resistance primarily included not only reduced CAFdATP production, but also increased antiapoptosis. The combination of CAFdA and ABT737 may be effective against CAFdA resistance.

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Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria

Cited by 105 publications

References 33 publications

Trimidox Induces Apoptosis via Cytochrome c Release in NALM‐6 Human B Cell Leukaemia Cells

Trimidox Induces Apoptosis via Cytochrome c Release in NALM‐6 Human B Cell Leukaemia Cells

Substrate specificity and phosphorylation of antiviral and anticancer nucleoside analogues by human deoxyribonucleoside kinases and ribonucleoside kinases

Novel leukemic cell lines resistant to clofarabine by mechanisms of decreased active metabolite and increased antiapoptosis

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