Poly ADP Ribose Polymerase (PARP) Inhibitors Induce Apoptosis Alone or Synergistically with Histone Deacetylase Inhibitors in Primary Acute Myeloid Leukemic Patient Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2974-2974 ◽  
Author(s):  
Terry J Gaymes ◽  
Sydney Shall ◽  
Farzin Farzaneh ◽  
Ghulam J Mufti
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Survival ◽  
Histone Deacetylase ◽  
Normal Control ◽  
Histone Deacetylase Inhibitors ◽  
Parp Inhibitors ◽  
Leukemic Cells ◽  
Acute Myeloid

Abstract It has been previously reported that cells defective for double strand break (dsb) DNA repair can be selectively targeted for apoptosis through abrogation of their PARP activity. It has also been reported that leukemic cells have inherent defects in dsb DNA repair. Exploitation of DNA repair defects using PARP inhibitors (PI) thus represents a specific and less toxic form of therapy for a number of hematological malignancies. In order to test the efficacy of PI therapy we analysed primary cells from acute myeloid leukemia (AML) patients and the potential for combination therapy with inhibitors of DNA methyltransferase (DNMTi) or histone deacetylase inhibitors (HDACi). We report that from a panel of 12 AML patients, 2 AML patient cells demonstrated abnormal cell cycle profiles and apoptosis in response to the PI, KU-0058948 (1μM). In contrast, normal control cells displayed standard cell cycle profiles and no apoptosis in response to PI. Clonogenic cytotoxicity assays also showed that these PI sensitive AML patient cells exhibited between 45–55% cell survival compared with 100% cell survival in control cells (p<0.05) in response to PI. The homologous recombination (HR) DNA repair component, rad51 forms foci in response to DNA damage. In HR compromised cells, rad51 foci fail to form. In response to PI, immunofluorescent studies show that the 2 PI sensitive AML patients cells demonstrated severely reduced rad51 foci formation (<1%) compared to PI insensitive and normal control cells (15%). This confirmed that PI targets the HR deficiencies in PI sensitive cells. Histone H2AX, phosphorylated in response to DSB had greatly increased foci formation in PI sensitive cells compared to PI insensitive control cells as a result of unrepaired DNA damage (32.3 vs 19.3%)(p<0.05). We next explored the use of PI in combination with DNMTi or HDACi. Whilst KU-0058948 offered only additive effects on DNMTi cytotoxicity, a non-cytotoxic concentration of KU-0058948 (10nM) behaved synergistically with HDACi potentiating the cytotoxic effect of MS275 by 45% compared to MS275 alone (p<0.05). Furthermore, non-cytotoxic doses of MS275 (50nM) potentiated the cytotoxic effects of KU-0058948 in PI sensitive cells (25–30%) compared to KU-0058948 alone (P<0.05). In conclusion, we have shown that primary AML cells are sensitive to the cytotoxic actions of PI. We have also showed that PI acts synergistically in combination with HDACi. PARP inhibitors can potentially exploit dsb repair defects in leukemic cells paving the way for a targeted therapy for leukemia.

Inhibition of Poly ADP Ribose Polymerase (PARP) Activity Exerts Cytotoxic Effects on Chromosomal Instability Syndrome and Leukaemic Cell Lines: Potential for Anti-Leukaemia Therapy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2647-2647
Author(s):  
Terry J. Gaymes ◽  
S. Shall ◽  
Farzin Farzaneh ◽  
Ghulam J. Mufti
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Survival ◽  
Cell Lines ◽  
Chromosomal Instability ◽  
Parp Inhibitors ◽  
Dna Breaks ◽  
Leukaemic Cells ◽  
Parp Activity

Abstract Recent reports suggest that BrCA1−/− and BrCA2−/− cells can be selectively targeted for cell death through abrogation of their PARP activity. It is postulated that as a result of PARP inhibition, accumulation of single strand DNA breaks (SSB) leads to the replication fork collapse and conversion of SSB to double strand DNA breaks (DSB). The inability of repair defective cells such as BrCA2−/− to repair the DSB would lead to cell death. Exploitation of DNA repair defects using PARP inhibitors (PI) thus represents a more specific and less toxic form of therapy for a number of haematological malignancies. Chromosomal instability (CI) syndromes that have inherent defects in double strand DNA repair also have a uniformly high incidence of transformation to acute leukaemia or lymphoma. In order to test the efficacy of PI therapy we analysed CI cell lines, myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) cell lines and the potential for combination therapy with inhibitors of DNA methyltransferase (DNMTi) or histone deacetylase inhibitors (HDACi). We report that cells from CI syndromes; Blooms syndrome, Fanconi Anaemia (FancD2 and FancA), Ataxia telancgectasia and Nijmegen break syndrome display abnormal cell cycle profiles and excessive apoptosis in response to the PI’s PJ34 (3μM) and EB47 (45μM). In contrast, normal control cells displayed standard cell cycle profiles and no apoptosis in response to PI at equivalent concentrations. Clonogenic cytotoxicity assays showed that CI syndrome cells exhibit between 30–75% cell survival compared with 100% cell survival in control cells (p<0.05) in response to PI. The homologous recombination (HR) DNA repair component, rad51 forms foci in response to DNA damage. In HR compromised cells, rad51 foci fail to form. In response to PI, immunofluorescent studies show that CI syndrome cells demonstrate severely reduced rad51 foci formation (<5%) compared to control cells (15%). This confirms that PI targets the HR deficiencies in CI syndrome cells. Histone γH2AX, phosphorylated in response to DSB had greatly increased foci formation in CI syndrome cells compared to control cells as a result of unrepaired DNA damage (25.3 vs 9.3%)(p<0.05). CI syndromes have increased transformation potential to the MDS and AML. Addition of 3μM PJ34 to the myelomonocytoid leukaemic/myelodysplastic cell line, P39 exhibited significant apoptosis, with a cell survival fraction of 65% compared to 100% in control cells (p<0.01). Immunofluorescent studies revealed reduced rad51 foci formation (6.3 vs 15%) and increased γH2AX foci formation (17.6 vs 9.3%)(p<0.01). Strikingly, we were also able to reproduce similar PI responses in the Jurkat T-cell leukaemic cell line. We next explored the use of PI in combination with DNMTi or HDACi. Whilst 3μM PJ34 offered only additive effects on decitabine cytotoxicity, a sub-optimal concentration (1μM) of PJ34 behaved synergistically with HDACi potentiating the cytotoxic effect of 200nM MS275 by 55% compared to MS275 alone (p<0.05) in P39 cells. In conclusion, we have shown that in a panel of CI syndrome and leukaemic cells, PI demonstrates significant cytotoxic responses. We also show that PI acts synergistically in combination with HDACi. Parp inhibitors can potentially exploit DSB repair defects in leukaemic cells paving the way for a targeted therapy for MDS and leukaemia.

Differential response of prostate cancer cells to ionizing radiation: The RB status.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 106-106
Author(s):  
Robert Benjamin Den ◽  
Steve Ciment ◽  
Ankur Sharma ◽  
Hestia Mellert ◽  
Steven McMahon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Ionizing Radiation ◽  
Cell Survival ◽  
Hormone Sensitive ◽  
Clonogenic Cell ◽  
Castrate Resistant

106 Background: Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in U.S. men. The retinoblastoma tumor suppressor protein, RB, plays a critical role in cell cycle regulation and loss of RB has been observed in 25-30% of prostate cancers. We have previously shown that RB loss results in a castrate resistant phenotype, however the consequences of RB status with regard to radiation response are unknown. We hypothesized that RB loss would downregulate the G1-S cell cycle checkpoint arrest normally induced by irradiation, inhibit DNA repair, and subsequently sensitize cells to ionizing radiation. Methods: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAP-C4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of RB using shRNA). Gamma H2AX assays were used to quantitate DNA damage and PARP cleavage and Caspase 3 were used to quantitate apoptosis. FACS analysis with BrdU was used to assess the cell cycle. Cell survival was measured using the clonogenic cell survival assay. In vivo work was performed in nude mice with tumor xenografts. Results: We observed that loss of RB increased radioresponsiveness in both transient and clonogenic cell survival assays in both hormone sensitive and castrate resistant cell lines (p<0.05). Cell death was not mediated through increased apoptosis nor was perturbations in cell cycle noted. However, loss of RB effected DNA repair as measured by gamma H2AX staining as well as cellular senescence. In vivo xenografts of the RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with single fraction of ionizing radiation in comparison to RB intact tumors (p<0.05). Conclusions: Loss of RB results in a differential response to ionizing radiation. Isogenic cells with RB knockdown are more sensitive to DNA damage and result in reduced cell survival. The underlying mechanism appears to be related to DNA damage repair and cellular senescence.

Histone Deacetylase Inhibitors Promote Abnormal Binding of DNA Repair Proteins to DNA Double Strand Breaks: Consequences for DNA Repair and Genomic Instability?.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 186-186
Author(s):  
Carine Robert ◽  
Ivana Gojo ◽  
Feyruz V. Rassool
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cell Lines ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Leukemia Cell ◽  
Leukemic Cells ◽  
Leukemia Cell Lines ◽  
Parp 1

Abstract Abstract 186 Histone Deacetylase inhibitors (HDi) affect gene expression through induction of histone acetylation and lead also to the acetylation of many other proteins which could affect their cellular activity. We have previously shown that HDi trigger in hematopoietic cells not only widespread histone acetylation and DNA damage responses, but actual DNA Double Strand Breaks (DSBs) which are significantly increased and persist for long periods of time compared with normal cells (Gaymes TJ. and al., Mol Cancer Res. 2006). This raises the hypothesis that HDi regulate the capacity of leukemic cells to repair DSBs, and the explanation for the increased and persistent DNA damage in leukemic cells may be that HDi directly acetylates proteins involved in DSB repair, thus decreasing repair activity. Non Homologous End-Joining (NHEJ) is one of the main pathways for the repair of DSBs in mammalian cells. While normal cells use NHEJ that is Ku and DNA-PKcs dependent, an alternative (Alt) NHEJ pathway (DNA-PKcs and Ku independent) involving Poly-ADP-Ribose Polymerase-1 (PARP-1), Werner syndrome helicase (WRN) and DNA LigaseIIIa proteins, has been identified and is responsible for deletions and translocations in cancer. We have recently reported that myeloid leukemia cells repair DSBs using this Alt NHEJ pathway (Sallmyr A. and al., Blood, 2008). Here we show that HDi treatment by Trichostatin A (300nM) results in differential acetylation of main NHEJ protein Ku70 in acute leukemia K562 cell line. In addition, PARP-1, active in several repair pathways, including single strand break repair and Alt NHEJ is also hyperacetylated in K562 cells after 1 and 6 hours of Trichostatin A treatment compared with control treatment. To investigate whether Trichostatin A treatment alters the binding of DNA repair proteins to DSBs, we used a chromatin immunoprecipitation (CHIP) assay in K562 cell line stably transfected with the DRNeo construct that can be induced to express a single DSB. Strikingly, CHIP analysis shows that PARP-1 is increased at the DSB after 1 hour of Trichostatin A treatment, compared with controls. Preliminary CHIP analysis for the protein XRCC1, necessary for the final step of Alt NHEJ repair, shows that it is decreased at the DSB site. Importantly, AML patients treated with the HDi MS-275 in vivo show significantly increased colocalization of PARP-1 and gH2A.x, a marker for DSBs, compared with pretreatment controls, confirming our in vitro data in leukemia cell lines. Altogether, these data suggest that HDi treatment leads to an increased presence of PARP-1 at DSBs, and that this may prevent subsequent critical repair steps, providing a possible explanation for the persistence of DNA damage. Finally, to determine whether DSB repair activity is indeed decreased with HDi treatment, we used an in vivo NHEJ repair assay in K562 and HL60 acute leukemia cell lines before and after treatment with Trichostatin A for 1 hour. Both leukemia cell lines demonstrate a significant decrease in the capacity of the cells to repair DSBs following Trichostatin A treatment. These results suggest that HDi result in both a physical and functional alteration of proteins participating in DNA repair pathways, leading to a decrease in NHEJ activity. The decrease in Alt NHEJ activity may have implications for genomic instability, diminishing abnormal repair following HDi treatment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 750
Author(s):  
Kiyohiro Ando ◽  
Akira Nakagawara
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Mitotic Catastrophe ◽  
Malignant Neoplasms ◽  
Checkpoint Kinases ◽  
Molecular Features ◽  
Cycle Checkpoint

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

scholarly journals HIV-1 Vpr activates host CRL4-DCAF1 E3 ligase to degrade histone deacetylase SIRT7

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiaohong Zhou ◽  
Christina Monnie ◽  
Maria DeLucia ◽  
Jinwoo Ahn
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Cell Cycle Arrest ◽  
Histone Deacetylase ◽  
E3 Ligase ◽  
Cycle Arrest ◽  
Wide Range ◽  
In Vitro Reconstitution ◽  
Hiv 1

Abstract Background Vpr is a virion-associated protein that is encoded by lentiviruses and serves to counteract intrinsic immunity factors that restrict infection. HIV-1 Vpr mediates proteasome-dependent degradation of several DNA repair/modification proteins. Mechanistically, Vpr directly recruits cellular targets onto DCAF1, a substrate receptor of Cullin 4 RING E3 ubiquitin ligase (CRL4) for poly-ubiquitination. Further, Vpr can mediate poly-ubiquitination of DCAF1-interacting proteins by the CRL4. Because Vpr-mediated degradation of its known targets can not explain the primary cell-cycle arrest phenotype that Vpr expression induces, we surveyed the literature for DNA-repair-associated proteins that interact with the CRL4-DCAF1. One such protein is SIRT7, a deacetylase of histone 3 that belongs to the Sirtuin family and regulates a wide range of cellular processes. We wondered whether Vpr can mediate degradation of SIRT7 via the CRL4-DCAF1. Methods HEK293T cells were transfected with cocktails of plasmids expressing DCAF1, DDB1, SIRT7 and Vpr. Ectopic and endogeneous levels of SIRT7 were monitered by immunoblotting and protein–protein interactions were assessed by immunoprecipitation. For in vitro reconstitution assays, recombinant CRL4-DCAF1-Vpr complexes and SIRT7 were prepared and poly-ubiqutination of SIRT7 was monitored with immunoblotting. Results We demonstrate SIRT7 polyubiquitination and degradation upon Vpr expression. Specifically, SIRT7 is shown to interact with the CRL4-DCAF1 complex, and expression of Vpr in HEK293T cells results in SIRT7 degradation, which is partially rescued by CRL inhibitor MNL4924 and proteasome inhibitor MG132. Further, in vitro reconstitution assays show that Vpr induces poly-ubiquitination of SIRT7 by the CRL4-DCAF1. Importantly, we find that Vpr from several different HIV-1 strains, but not HIV-2 strains, mediates SIRT7 poly-ubiquitination in the reconstitution assay and degradation in cells. Finally, we show that SIRT7 degradation by Vpr is independent of the known, distinctive phenotype of Vpr-induced cell cycle arrest at the G2 phase, Conclusions Targeting histone deacetylase SIRT7 for degradation is a conserved feature of HIV-1 Vpr. Altogether, our findings reveal that HIV-1 Vpr mediates down-regulation of SIRT7 by a mechanism that does not involve novel target recruitment to the CRL4-DCAF1 but instead involves regulation of the E3 ligase activity.

scholarly journals The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 479
Author(s):  
Pavel Vodicka ◽  
Ladislav Andera ◽  
Alena Opattova ◽  
Ludmila Vodickova
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Dna Lesions ◽  
Cell Cycle Checkpoint ◽  
Solid Cancer ◽  
Genomic Integrity ◽  
Repair Capacity ◽  
Mutational Status ◽  
Telomere Homeostasis

The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for both cancer development and chemotherapy outcome. DDR represents the complex events that detect DNA lesions and activate signaling networks (cell cycle checkpoint induction, DNA repair, and induction of cell death). TP53, the guardian of the genome, governs the cell response, resulting in cell cycle arrest, DNA damage repair, apoptosis, and senescence. The mutational status of TP53 has an impact on DDR, and somatic mutations in this gene represent one of the critical events in human carcinogenesis. Telomere dysfunction in cells that lack p53-mediated surveillance of genomic integrity along with the involvement of DNA repair in telomeric DNA regions leads to genomic instability. While the role of individual players (DDR, telomere homeostasis, and TP53) in human cancers has attracted attention for some time, there is insufficient understanding of the interactions between these pathways. Since solid cancer is a complex and multifactorial disease with considerable inter- and intra-tumor heterogeneity, we mainly dedicated this review to the interactions of DNA repair, telomere homeostasis, and TP53 mutational status, in relation to (a) cancer risk, (b) cancer progression, and (c) cancer therapy.

CBIO-22. PARP INHIBITION SYNERGIZES WITH DNA DAMAGING DRUGS IN PEDIATRIC CNS TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi31-vi31
Author(s):  
Anna Laemmerer ◽  
Dominik Kirchhofer ◽  
Sibylle Madlener ◽  
Daniela Loetsch-Gojo ◽  
Carola Jaunecker ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Predictive Biomarkers ◽  
High Grade Glioma ◽  
Parp Inhibitors ◽  
Cns Tumors ◽  
Parp Inhibition ◽  
Tumor Subtypes ◽  
Synergistic Cytotoxicity ◽  
Anti Cancer

Abstract BACKGROUND Central nervous system (CNS) tumors are the second most common childhood cancer. Despite innovations in surgery and chemo-/radiotherapy, CNS tumors remain the major cause of cancer-related death in children. Previous sequencing analyses in a pediatric cancer cohort identified BRCA and DSB repair signatures as potentially targetable events. Based on these findings, we propose the use of PARP inhibitors (PARPi) for aggressive CNS tumor subtypes, including high-grade glioma (HGG), medulloblastoma (MB) and ependymoma (EPN). METHODS We tested multiple PARPi in tumor cell lines (n=8) as well as primary patient-derived models (n=11) of pediatric HGG, MB, EPN and atypical teratoid/rhabdoid tumors (ATRTs). Based on PARPi sensitivity, selected models were further exposed to a combination of PARPi and DNA-damaging/modifying agents. The mode of action was investigated using Western blot and flow cytometry. RESULTS We show that a fraction of pediatric MB, EPN and ATRT demonstrate sensitivity towards PARP inhibition, which is paralleled by susceptibility to the DNA damaging drugs cisplatin and irinotecan. Interestingly, talazoparib, the most potent PARPi, showed synergistic cytotoxicity with DNA-damaging/modifying drugs. In addition, cell cycle blockade and increased DNA damage combined with reduced DNA repair signaling, such as activation of the ATR/Chk1 pathway were observed. Corroboratively, talazoparib exhibited a synergistic anti-cancer effect in combination with inhibitors of ATR, a major regulator of DNA damage response. CONCLUSION/OUTLOOK To sum up, we demonstrate that PARP inhibition synergizes with DNA damaging anti-cancer compounds or DNA repair inhibitors and, thus, represents a promising therapeutic strategy for a defined subgroup of pediatric high-risk CNS tumors patients. More in depth characterization of the underlying molecular events will most likely allow the identification of predictive biomarkers for most efficient implementation of this strategy into clinical application.

Octadecyloxyethyl Adefovir Exhibits Potent in vitro and in vivo Cytotoxic Activity and Has Synergistic Effects with Ara-C in Acute Myeloid Leukemia

Chemotherapy ◽  
2018 ◽  
Vol 63 (4) ◽  
pp. 225-237 ◽  
Author(s):  
Haytham Khoury ◽  
Ruijuan He ◽  
Aaron Schimmer ◽  
James R. Beadle ◽  
Karl Y. Hostetler ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Cell Cycle Arrest ◽  
Clinical Benefit ◽  
Myeloid Leukemia ◽  
Mouse Bone Marrow ◽  
Medical Needs ◽  
Cycle Arrest ◽  
Acute Myeloid

Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50–70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this screen, we discovered adefovir dipi­voxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcome the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir were highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of > 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was through cell cycle arrest and DNA damage. Indeed, ODE-adefovir treatment induced cell cycle arrest in the S phase and increased levels of pH2Ax, indicating the induction of DNA damage. Furthermore, there was an increase in phospho-p53, transactivation of proapoptotic genes and activation of the intrinsic apoptotic pathway. Subsequent investigation unveiled strong synergism between ODE-adefovir and ara-C, making their coadministration of potential clinical benefit. Expression of MRP4, a nucleoside transporter, appeared to influence the response of AML cells to ODE-adefovir, as its inhibition potentiated ODE-adefovir killing. Taken together, our findings indicate that clinical development of ODE-adefovir or related compounds for the treatment of AML is warranted.

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