The Antileukemia Drug 2-Chloro-2′-deoxyadenosine: An Intrinsic Transcriptional Antagonist

Hartman, William R.; Hentosh, Patricia

doi:10.1124/mol.65.1.227

Cited by 19 publications

(9 citation statements)

References 37 publications

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“…Results from RNA profiling studies also suggest that DCK levels are high in T cells, B cells and dendritic cells but low in nonhematologic cell types such as liver, brain, lung, heart, skin, kidney and germ cells [7], [8], which may have an advantage of reduced adverse events related to these organs for 2-CDA. The mechanism by which 2-CdATP induces cell death appears to be through DNA double strand breaks, failure to repair them and disruption of DNA synthesis by inhibition of key enzymes involved in DNA and RNA synthesis and repair such as DNA polymerase and ribonucleotide reductase [9]–[11]. 2-CDA can induce cell death at clinically relevant concentrations through apoptosis by depleting intracellular pools of nicotinamide adenine dinucleotide and adenosine triphosphate [12].…”

Section: Introductionmentioning

confidence: 99%

Chronic Cladribine Administration Increases Amyloid Beta Peptide Generation and Plaque Burden in Mice

et al. 2012

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BackgroundThe clinical uses of 2-chloro-2′-deoxyadenosine (2-CDA) or cladribine which was initially prescribed to patients with hematological and lymphoid cancers is now extended to treat patients with multiple sclerosis (MS). Previous data has shown that 2-CDA has high affinity to the brain and readily passes through the blood brain barrier reaching CSF concentrations 25% of that found in plasma. However, whether long-term administration of 2-CDA can lead to any adverse effects in patients or animal models is not yet clearly known.MethodologyHere we show that exposure of 2-CDA to CHO cells stably expressing wild-type APP751 increased generation and secretion of amyloid β peptide (Aβ) in to the conditioned medium. Interestingly, increased Aβ levels were noticed even at non-toxic concentrations of 2-CDA. Remarkably, chronic treatment of APdE9 mice, a model of Alzheimer's disease with 2-CDA for 60 days increased amyloid plaque burden by more than 1-fold. Increased Aβ generation appears to result from increased turnover of APP as revealed by cycloheximide-chase experiments. Additionally, surface labeling of APP with biotin and immunoprecipitation of surface labeled proteins with anti-biotin antibody also indicated increased APP at the cell surface in 2-CDA treated cells compared to controls. Increased turnover of APP by 2-CDA in turn might be a consequence of decreased protein levels of PIN 1, which is known to regulate cis-trans isomerization and phosphorylation of APP. Most importantly, like many other oncology drugs, 2-CDA administration led to significant delay in acquiring a reward-based learning task in a T maze paradigm.ConclusionsTaken together, these data provide compelling evidence for the first time that chronic 2-CDA administration can increase amyloidogenic processing of APP leading to robustly increased plaque burden which may be responsible for the observed deficits in learning skills. Thus chronic treatment of mice with 2-CDA can have deleterious effects in vivo.

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Section: Introductionmentioning

confidence: 99%

Chronic Cladribine Administration Increases Amyloid Beta Peptide Generation and Plaque Burden in Mice

et al. 2012

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“…They also cooperate with cytochrome c and apoptosis protein-activated factor-1 (Apaf-1) to initiate the intrinsic pathway of apoptosis [7,8]. Lastly, purine NAs, mainly fludarabine, inhibit RNA and protein synthesis, which could contribute to their cytotoxicity by reducing the synthesis of proteins that are essential for cell survival [9,10]. The diversity of these effects can explain why purine NAs are efficient towards both proliferating and quiescent cells.…”

Section: Introductionmentioning

confidence: 99%

Nucleoside analogs induce proteasomal down-regulation of p21 in chronic lymphocytic leukemia cell lines

Bastin-Coyette

Cardoen

Smal

et al. 2011

Biochemical Pharmacology

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Nucleoside analogs (NAs) represent an important class of anticancer agents that induce cell death after conversion to triphosphate derivatives. One of their most important mechanisms of action is the activation of p53, leading to apoptosis through the intrinsic pathway. Classically, the activation of p53 also induces p21 accumulation, which leads to cell cycle arrest at the G1/S transition. In previous work, we observed that 2-chloro-2'-deoxyadenosine (CdA), a NA with high activity in lymphoid disorders, including chronic lymphocytic leukemia (CLL), promotes the G1/S transition in the CLL cell line EHEB at cytotoxic concentrations. This finding led us to investigate the p21 response to NAs in these cells. We show here that CdA, but also fludarabine, gemcitabine, and cytarabine, strongly reduced the p21 protein level in EHEB cells as well as in JVM-2 cells, another CLL cell line. This p21 depletion occurred despite induction of p53 and increase of p21 mRNA and was prevented by proteasome inhibitors. Increase of proteasomal degradation caused by NAs appeared to be ubiquitinindependent. Also, NAs induced in these cells an increase of cyclin-dependent kinase (Cdk2) activity and a monoubiquitination of cell proliferating nuclear antigen (PCNA), two processes that are negatively regulated by p21. These changes were not observed with other p53 activators, like etoposide and nutlin-3a that increased the p21 protein level. In conclusion, our study reveals that NAs can induce an alternative pattern of cellular response in some cell models.

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“…Also, cladribine is phosphorylated and incorporated into cellular DNA and acts as a transcriptional antagonist. 62 It causes apoptosis in leukemia cells. Its efficacy, however, is compromised by the emergence of resistant cells, which do not undergo apoptosis.…”

Section: Velcade/bortezomib (Ps-341)mentioning

confidence: 99%

Analysis of FDA Approved Anticancer Drugs Reveals the Future of Cancer Therapy

Blagosklonny¹

2004

Cell Cycle

125

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This review discusses 26 new anticancer drugs approved by the FDA in the past decade. Based on their targets, these anticancer agents can be divided into three groups. The first group contains cancer-selective or semi-selective drugs that are effective in rare kinase-addictive cancers. For other malignancies, semi-selective drugs have to be judiciously combined with nonselective agents. The second group includes analogs of classic cytotoxic agents such as DNA alkylating agents, nucleoside analogs and anti-microtubule agents. As expected, they have a marginal advantage over the existing cytotoxic drugs, nevertheless are more effective (in common cancers) than semi-selective agents. The third is a diverse group of tissue-selective agents that essentially attack the normal tissues of tumor origin and thus exploit the tissue-specific similarities between normal and cancer cells. Our analysis predicts that monotherapy with semi-selective agents will be limited to rare cancers. In most cancers, however, two anticancer strategies may be most fruitful: (a) combinations of cytotoxic drugs with semi-selective agents aimed at matching targets and (b) tissue-selective therapy aimed at normal and tumor cells of the same tissues.

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The Antileukemia Drug 2-Chloro-2′-deoxyadenosine: An Intrinsic Transcriptional Antagonist

Cited by 19 publications

References 37 publications

Chronic Cladribine Administration Increases Amyloid Beta Peptide Generation and Plaque Burden in Mice

Chronic Cladribine Administration Increases Amyloid Beta Peptide Generation and Plaque Burden in Mice

Nucleoside analogs induce proteasomal down-regulation of p21 in chronic lymphocytic leukemia cell lines

Analysis of FDA Approved Anticancer Drugs Reveals the Future of Cancer Therapy

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