High PARP-1 expression predicts poor survival in acute myeloid leukemia and PARP-1 inhibitor and SAHA-bendamustine hybrid inhibitor combination treatment synergistically enhances anti-tumor effects

Li, Xia; Li, Chenying; Wang, Jinghan; Huang, Jiansong; Ma, Zeyu; Huang, Xin; He, Xiao; Zhou, Yile; Xu, Yu; Yu, Mengxia; Huang, Shujuan; Yan, Xiao; Li, Fenglin; Pan, Jiajia; Wang, Yungui; Yu, Yongsheng; Jin, Jie

doi:10.1016/j.ebiom.2018.11.025

Cited by 53 publications

(38 citation statements)

References 60 publications

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“…The latest data also confirm that PARP1 was highly expressed in cytogenetically normal AML patients and AML cell lines compared to normal bone marrow cells. It may indicate that PARP1 plays a critical role in the development of AML [4]. Research by Fonfria et al [35] confirms the hypothesis that PARP enzyme activity is a central component of the pathway linking oxidative stress with TRPM2 activation [35].…”

Section: Discussionmentioning

confidence: 84%

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Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells

et al. 2020

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Background: Acute myeloid leukemia (AML) is a heterogenic lethal disorder characterized by the accumulation of abnormal myeloid progenitor cells in the bone marrow which results in hematopoietic failure. Despite various efforts in detection and treatment, many patients with AML die of this cancer. That is why it is important to develop novel therapeutic options, employing strategic target genes involved in apoptosis and tumor progression. Methods: The aim of the study was to evaluate PARP1, PARP2, PARP3, and TRPM2 gene expression at mRNA level using qPCR method in the cells of hematopoietic system of the bone marrow in patients with acute myeloid leukemia, bone marrow collected from healthy patients, peripheral blood of healthy individuals, and hematopoietic stem cells from the peripheral blood after mobilization. Results: The results found that the bone marrow cells of the patients with acute myeloid leukemia (AML) show overexpression of PARP1 and PARP2 genes and decreased TRPM2 gene expression. In the hematopoietic stem cells derived from the normal marrow and peripheral blood after mobilization, the opposite situation was observed, i.e. TRPM2 gene showed increased expression while PARP1 and PARP2 gene expression was reduced. We observed positive correlations between PARP1, PARP2, PARP3, and TRPM2 genes expression in the group of mature mononuclear cells derived from the peripheral blood and in the group of bone marrow-derived cells. In AML cells significant correlations were not observed between the expression of the examined genes. In addition, we observed that the reduced expression of TRPM2 and overexpression of PARP1 are associated with a shorter overall survival of patients, indicating the prognostic significance of these genes expression in AML. Conclusions: Our research suggests that in physiological conditions in the cells of the hematopoietic system there is mutual positive regulation of PARP1, PARP2, PARP3, and TRPM2 genes expression. PARP1, PARP2, and TRPM2 genes at mRNA level deregulate in acute myeloid leukemia cells.

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Section: Discussionmentioning

confidence: 84%

“…Hence, it is recommended to use PARP inhibitors (PARPi) in the treatment of tumors, in particular those that do not have the ability to recombine (homologous recombination -HR) due to the mutations causing loss of BRCA1 or BRCA2 function. This phenomenon is referred to as synthetic lethality [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells

et al. 2020

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“…In both t(8;21)/inv16 AML and NB, tumors high KIT expression is strongly associated with DNA repair mechanisms and processes of cell cycle regulation. In NB tumors, high activity of DNA damage repair is associated with a worse prognosis for overall patient survival, and there are some reports that argue that targeting DNA damage repair may be beneficial for a subset of AMLs (63, 64). It is possible that high activity of DNA damage repair and NGF signaling pathways can be a transcriptomic signature of MYCN -amplified NB (65, 66).…”

Section: Discussionmentioning

confidence: 99%

Two Receptors, Two Isoforms, Two Cancers: Comprehensive Analysis of KIT and TrkA Expression in Neuroblastoma and Acute Myeloid Leukemia

et al. 2019

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Pediatric cancers represent a wide variety of different tumors, though they have unique features that distinguish them from adult cancers. Receptor tyrosine kinases KIT and TrkA functions in AML and NB, respectively, are well-characterized. Though expression of these receptors is found in both tumors, little is known about KIT function in NB and TrkA in AML. By combining gene enrichment analysis with multidimensional scaling we showed that pediatric AMLs with t(8;21) or inv16 and high KIT expression levels stand out from other AML subtypes as they share prominent transcriptomic features exclusively with KIT-overexpressing NBs. We showed that AML cell lines had a predominant expression of an alternative TrkAIII isoform, which reportedly has oncogenic features, while NB cell lines had dominating TrkAI-II isoforms. NB cells, on the other hand, had an abnormal ratio of KIT isoforms as opposed to AML cells. Both SCF and NGF exerted protective action against doxorubicin and cytarabine for t(8;21) AML and NB cells. We identified several gene sets both unique and common for pediatric AML and NB, and this expression is associated with KIT or TrkA levels. NMU, DUSP4, RET, SUSD5, NOS1, and GABRA5 genes are differentially expressed in NBs with high KIT expression and are associated with poor survival in NB. We identified HOXA10, BAG3, and MARCKS genes that are connected with TrkA expression and are marker genes of poor outcome in AML. We also report that SLC18A2, PLXNC1, and MRPL33 gene expression is associated with TrkA or KIT expression levels in both AML and NB, and these genes have a prognostic value for both cancers. Thus, we have provided a comprehensive characterization of TrkA and KIT expression along with the oncogenic signatures of these genes across two pediatric tumors.

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“…NL-101, which was developed by replacing the side chain of the alkylating agent Bendamustine with the hydroxamic acid of Vorinostat, presenting properties related to HDAC inhibition, DNA damage, and induced apoptosis of leukemic cells. The combination of the SAHA–Bendamustine hybrid inhibitor with the PARP inhibitor BMN673 had a strong synergistic effect in AML, inducing apoptosis and arresting cell cycle in vitro and prolonging mouse survival in vivo [164]. Once more, the mechanism of action of this drug is the induction of DNA damage.…”

Section: Histone Deacetylase Inhibitors (Hdaci): Mechanism Of Actimentioning

confidence: 99%

HDAC Inhibitors in Acute Myeloid Leukemia

José‐Eneriz

Gimenez-Camino

Agirre

et al. 2019

Cancers

142

114

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Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents.

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High PARP-1 expression predicts poor survival in acute myeloid leukemia and PARP-1 inhibitor and SAHA-bendamustine hybrid inhibitor combination treatment synergistically enhances anti-tumor effects

Cited by 53 publications

References 60 publications

Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells

Different regulation of PARP1, PARP2, PARP3 and TRPM2 genes expression in acute myeloid leukemia cells

Two Receptors, Two Isoforms, Two Cancers: Comprehensive Analysis of KIT and TrkA Expression in Neuroblastoma and Acute Myeloid Leukemia

HDAC Inhibitors in Acute Myeloid Leukemia

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