Targeting DNA repair with aphidicolin sensitizes primary chronic lymphocytic leukemia cells to purine analogs

Starczewska, Eliza; Beyaert, Maxime; Michaux, Lucienne; Vekemans, Marie-Christiane; Saussoy, Pascale; Bol, Vanesa; Echarri, Ainhoa Arana; Smal, Caroline; Neste, Éric Van Den; Bontemps, Françoise

doi:10.18632/oncotarget.9525

Cited by 10 publications

(7 citation statements)

References 49 publications

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“…Induction of γH2AX in response to purine analogs in primary CLL cells has been reported in several studies [ 37 – 39 ]. We show here that γH2AX accumulation, whether induced by fludarabine (Figure 3C , left panel) or cladribine (Figure 3C , right panel), was significantly reduced by the ATR inhibitor VE-821.…”

Section: Resultsmentioning

confidence: 99%

Reevaluation of ATR signaling in primary resting chronic lymphocytic leukemia cells: evidence for pro-survival or pro-apoptotic function

et al. 2017

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ATM, primarily activated by DNA double-strand breaks, and ATR, activated by single-stranded DNA, are master regulators of the cellular response to DNA damage. In primary chronic lymphocytic leukemia (CLL) cells, ATR signaling is considered to be switched off due to ATR downregulation. Here, we hypothesized that ATR, though expressed at low protein level, could play a role in primary resting CLL cells after genotoxic stress. By investigating the response of CLL cells to UV-C irradiation, a prototypical activator of ATR, we could detect phosphorylation of ATR at Thr-1989, a marker for ATR activation, and also observed that selective ATR inhibitors markedly decreased UV-C-induced phosphorylation of ATR targets, including H2AX and p53. Similar results were obtained with the purine analogs fludarabine and cladribine that were also shown to activate ATR and induce ATR-dependent phosphorylation of H2AX and p53. In addition, ATR inhibition was found to sensitize primary CLL cells to UV-C by decreasing DNA repair synthesis. Conversely, ATR inhibition rescued CLL cells against purine analogs by reducing expression of the pro-apoptotic genes PUMA and BAX. Collectively, our study indicates that ATR signaling can be activated in resting CLL cells and play a pro-survival or pro-apoptotic role, depending on the genotoxic context.

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Section: Resultsmentioning

confidence: 99%

Reevaluation of ATR signaling in primary resting chronic lymphocytic leukemia cells: evidence for pro-survival or pro-apoptotic function

et al. 2017

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“…The first step of activating cladribine is catalyzed by deoxycytidine kinase (dCK). This enzyme is mainly expressed in lymphocytes, whereas cladribine is particularly active in lymphoid tissues 11 . Genotoxic agents, including UV-C and DNA synthesis inhibitors or cladribine contribute to increase of ATR (Ataxia Telangiectasia and Rad3-related protein) kinase activity, which is a major activator of dCK in leukemic cells 5,12 .…”

Section: Introductionmentioning

confidence: 99%

Antileukemic activity of novel adenosine derivatives

Poczta

Rogalska

Łukawska

et al. 2019

Sci Rep

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The present study investigated the effect of cladribine (CLA) and six of its derivatives containing a formamidine group at position 6 (CLA-FDM, CLA-FPAZ, CLA-FPIR, CLA-FPIP, CLA-FHEX, and CLA-FMOR) on acute promyelocytic, lymphoblastic, and acute monocytic leukemia cells. The role of ATR kinase in deoxycytidine kinase (dCK) activation in response to DNA damage was assessed. The presence of DNA lesions was assessed by measurement phosphorylation of H2AX and by using the alkaline comet assay with proteinase K post-treatment following assessment of the cell cycle. Apoptotic events such as alterations in intracellular calcium concentration, caspase-3/7 activity and increased sub-G1 cell population were measured. CLA derivatives were highly effective against leukemic cells, showing high cytotoxicity, causing DNA fragmentation, and inducing DNA-protein cross-links in leukemic cells. CLA-FMOR showed the highest efficacy. CLA derivatives increased the levels of intracellular calcium ions, caspase-3/7 and the percentage of sub-G1 apoptotic cells and blocked cells in the S phase of the cell cycle to a greater extent than free CLA. The selective ATR inhibitor VE-821 significantly suppressed the increase in dCK activity and decreased basal dCK activity. The present results suggested that ATR kinase controls dCK activity in response to synthetic CLA derivatives.

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“…It is already known that aphidicolin acts synergistically to improve the sensitivity and cytotoxic potential of purine analogs and platinum compounds (25). It is also established that entinostat, a…”

Section: Chemo-radiotherapy Treated Samples Have Higher Incidence Of mentioning

confidence: 99%

1q21.3 amplification modulates therapy sensitivity in Triple Negative Breast Cancer

Venkata

Ghersi²,

Ganti³

et al. 2020

Preprint

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The contrast in therapy sensitivity and response across triple negative breast cancer (TNBC) patients suggest underlying genotypic heterogeneity. Using publicly available data, we found significant associations between DNA-level copy number alterations of 1q21.3 locus and therapy sensitivity. We show that in spite of their aggressive nature, 1q21.3 amplified tumors are more responsive to commonly used cytotoxic therapies, highlighting the relevance of 1q21.3 copy number status as a genetic marker for risk stratification, therapy selection and response.

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Targeting DNA repair with aphidicolin sensitizes primary chronic lymphocytic leukemia cells to purine analogs

Cited by 10 publications

References 49 publications

Reevaluation of ATR signaling in primary resting chronic lymphocytic leukemia cells: evidence for pro-survival or pro-apoptotic function

Reevaluation of ATR signaling in primary resting chronic lymphocytic leukemia cells: evidence for pro-survival or pro-apoptotic function

Antileukemic activity of novel adenosine derivatives

1q21.3 amplification modulates therapy sensitivity in Triple Negative Breast Cancer

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