A New Mechanism of Toxicity of 2-Chlorodeoxyadenosine (2CdA)

Fabianowska‐Majewska, Krystyna; Wasiak, T.; Warzocha, Krzysztof; Marlewski, M; Fairbanks, Lynette D.; Smoleński, Ryszard T.; Duley, John A.; Simmonds, Anne

doi:10.1007/978-1-4615-2584-4_28

Cited by 6 publications

(4 citation statements)

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“…S7 ). At low doses, cladribine inhibits the activity of S-adenosylhomocysteine hydrolase, a key enzyme in the biosynthesis pathway of S-adenosylmethionine (SAM), which constitutes a methyl group donor in DNA methylation reactions 18 – 20 , 35 . Therefore we determined, whether cladribine compromises DNA methylation by affecting the cellular SAM level.…”

Section: Resultsmentioning

confidence: 99%

“…The activity of cladribine has been mostly attributed to increased bioactivation of AraC in leukemic blasts as well as direct inhibition of DNA synthesis 17 . Importantly, cladribine exhibits DNA hypomethylating activity due to its ability to inhibit S-adenosylhomocysteine hydrolase (SAHH) and to reduce the pool of active methyl donor S-adenosylmethionine (SAM) in leukemic cells 18 – 21 . Our group has demonstrated in previous PALG studies that DAC was associated with increased complete remission (CR) rate and prolonged overall survival (OS), with the most significant benefit in patients with unfavorable cytogenetics 15 , 16 .…”

Section: Introductionmentioning

confidence: 99%

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IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen

Libura

Białopiotrowicz

Giebel

et al. 2021

Sci Rep

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Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients’ outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37–0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen

Libura

Białopiotrowicz

Giebel

et al. 2021

Sci Rep

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“…An original mechanism of 2-CdA cytotoxicity is related to the inhibition of ADA and S-adenosylhomocysteine hydrolase (SAHH). 64 Inhibition of ADA could lead to increased levels of Ado and dAdo, thereby causing the inactivation of SAHH and reduced homocysteine formation. This might result in altered methylation reactions and indirectly inhibit nucleotide synthesis and cellular proliferation.…”

Section: Figurementioning

confidence: 99%

Nucleoside analogues: mechanisms of drug resistance and reversal strategies

2001

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“…Moreover, MtnP from human liver can catalyze the phosphorylase reaction with adenosine as substrate. 12) Taken together, enzymatic analyses of MSP enzymes suggest that ribose and adenosine metabolism, linked with amino acid synthesis, are found in both prokaryotes and eukaryotes.…”

Section: )mentioning

confidence: 99%

Plausible Novel Ribose Metabolism Catalyzed by Enzymes of the Methionine Salvage Pathway inBacillus subtilis

Nakano

Saito

Yokota

et al. 2013

Bioscience, Biotechnology, and Biochemistry

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The methionine salvage pathway (MSP) recycles reduced sulfur from 5-methylthioribose. Here we propose a novel ribose metabolic pathway performed by MSP enzymes of Bacilli. MtnK, an initial catalyst of MSP, had significant ribose kinase activity, with V max and K m values of 2.9 mol min À1 mg of protein À1 and 4.8 mM. Downstream enzymes catalyzed the isomerization of ribose-1-phosphate and subsequent dehydration, enolization, dephosphorylation, and dioxygenation.Key words: methionine salvage pathway; Bacillus subtilis; ribose; 5-methylthioriboseThe most living organisms utilize the methionine salvage pathway (MSP) to recycle reduced sulfur from a by-product of polyamine synthesis, 5-methylthioribose (MTR). 1) Our previous study identified that six enzymes coded from two neighboring MSP operons, mtnKA and mtnWXBD, catalyze sequential metabolic steps in the MSP of Bacillus subtilis (Fig. 1). 2,3) In this pathway, MtnK (MTR kinase), MtnA (isomerase), MtnB (dehydratase), MtnW (enolase), MtnX (phosphatase), MtnD (dioxygenase), and various aminotransferases regenerate methionine from MTR.X-Ray crystallographic analyses of MSP enzymes revealed that MtnK, MtnA, and MtnW (PDB: 2PUN, 2YVK, and 2ZVI respectively) possess specific hydrophobic pockets recognizing the methylthio groups of each substrate, but recent 1 H-NMR analysis has revealed that ribose (which possesses a 5-hydroxy group instead of a 5-methylthio group) is converted to 2-hydroxy-3-keto-5-hydroxypentenyl-1-phosphate (HK-HPenyl-1-P) by reaction of MtnK, MtnA, MtnB, and MtnW from B. subtilis.4) These results suggest that MSP enzymes recognize substrate derivatives with both the 5-methylthio and the 5-hydroxy group. Hence we hypothesize that all MSP enzymes coded from the two mtn operons sequentially catalyze the six reactions using ribose as initial substrate in the pathway (Fig. 1). In the proposed ribose metabolic pathway, MtnK phosphorylates ribose to yield ribose-1-phosphate (R-1-P), with ATP as the phosphoryl donor. R-1-P aldose is isomerized to ribulose-1-phosphate (Ru-1-P) ketose by MtnA, and subsequently MtnB removes H 2 O from Ru-1-P, generating 2,3-diketo-5-hydroxypentyl-1-phosphate (DK-HP-1-P). At the next step, MtnW generates HK-HPenyl-1-P from DK-HP-1-P. In addition to these four reported reactions of MtnK to MtnW, 4) HK-HPenyl-1-P is dephosphorylated by MtnX, producing 1,2-dihydroxy-3-keto-5-hydroxypentene (DHK-HPene). DHK-HPene is finally converted to formate and the homoserine precursor, 2-keto-4-hydroxybutyrate (KHB), by the Fe 2þ -bound form of MtnD. Our hypothesis suggests the possibility of a novel ribose metabolic pathway in which ribose is converted to the key metabolite, homoserine. To address this possibility, we investigated (i) enzymatic properties of MtnK and MtnA for their activities towards ribose and R-1-P, and (ii) the dehydration, enolization, dephosphorylation, and dioxygenation activities of the MSP enzymes to identify the downstream metabolites derived from ribose. Before the enzymatic assays, histidinetagged MtnK, MtnA, MtnB...

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A New Mechanism of Toxicity of 2-Chlorodeoxyadenosine (2CdA)

Cited by 6 publications

References 6 publications

IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen

IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen

Nucleoside analogues: mechanisms of drug resistance and reversal strategies

Plausible Novel Ribose Metabolism Catalyzed by Enzymes of the Methionine Salvage Pathway inBacillus subtilis

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