Combination of a hypomethylating agent and inhibitors of PARP and HDAC traps PARP1 and DNMT1 to chromatin, acetylates DNA repair proteins, down-regulates NuRD and induces apoptosis in human leukemia and lymphoma cells

Valdez, Benigno C.; Li, Yang; Murray, David; Liu, Yan; Nieto, Yago; Champlin, Richard E.; Andersson, Börje S.

doi:10.18632/oncotarget.23386

Cited by 41 publications

(34 citation statements)

References 41 publications

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“…Combined therapies have shown synergistic effects in peripheral T-cell lymphoma, resulting in the enhanced induction of lymphoma cell apoptosis [ 136 , 137 ]. Benigno C. Valdez et al reported that the combination of a hypomethylating agent, decitabine (DAC), a PARP inhibitor and an HDAC synergistically inhibited cell proliferation and induced apoptosis in human leukaemia and lymphoma cells [ 138 ]. A phase I study investigated oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with PTCL and showed that combination epigenetic modifying drug therapy exhibited marked activity in patients with PTCL [ 139 ].…”

Section: Dna Methylationmentioning

confidence: 99%

Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma

Zhang

2020

Clin Epigenet

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Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of clinically aggressive diseases associated with poor prognosis. Except for ALK + anaplastic large-cell lymphoma (ALCL), most peripheral T-cell lymphomas are highly malignant and have an aggressive disease course and poor clinical outcomes, with a poor remission rate and frequent relapse after first-line treatment. Aberrant epigenetic alterations play an important role in the pathogenesis and development of specific types of peripheral T-cell lymphoma, including the regulation of the expression of genes and signal transduction. The most common epigenetic alterations are DNA methylation and histone modification. Histone modification alters the level of gene expression by regulating the acetylation status of lysine residues on the promoter surrounding histones, often leading to the silencing of tumour suppressor genes or the overexpression of proto-oncogenes in lymphoma. DNA methylation refers to CpG islands, generally leading to tumour suppressor gene transcriptional silencing. Genetic studies have also shown that some recurrent mutations in genes involved in the epigenetic machinery, including TET2, IDH2-R172, DNMT3A, RHOA, CD28, IDH2, TET2, MLL2, KMT2A, KDM6A, CREBBP, and EP300, have been observed in cases of PTCL. The aberrant expression of miRNAs has also gradually become a diagnostic biomarker. These provide a reasonable molecular mechanism for epigenetic modifying drugs in the treatment of PTCL. As epigenetic drugs implicated in lymphoma have been continually reported in recent years, many new ideas for the diagnosis, treatment, and prognosis of PTCL originate from epigenetics in recent years. Novel epigenetic-targeted drugs have shown good tolerance and therapeutic effects in the treatment of peripheral T-cell lymphoma as monotherapy or combination therapy. NCCN Clinical Practice Guidelines also recommended epigenetic drugs for PTCL subtypes as second-line therapy. Epigenetic mechanisms provide new directions and therapeutic strategies for the research and treatment of peripheral T-cell lymphoma. Therefore, this paper mainly reviews the epigenetic changes in the pathogenesis of peripheral T-cell lymphoma and the advancement of epigenetic-targeted drugs in the treatment of peripheral T-cell lymphoma (PTCL).

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Section: Dna Methylationmentioning

confidence: 99%

Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma

Zhang

2020

Clin Epigenet

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“…HDACi enhances Ku70 acetylation, abolishes DNA repair, increases the levels of DNA damage protein H2AX phosphorylation (γ-H2AX) [128,129,130,131,132], and leads to cell cycle arrest and apoptosis [111,133,134]. MS-275 dramatically elevates Ku70 acetylation and Bax activation in medulloblastoma cells [106].…”

Section: Ku70 Acetylation By Hdaci Treatmentmentioning

confidence: 99%

Apoptosis Induction byHistone Deacetylase Inhibitors in Cancer Cells: Role of Ku70

Gong

Wang

Jing

2019

IJMS

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Histone deacetylases (HDACs) are a group of enzymes that regulate gene transcription by controlling deacetylation of histones and non-histone proteins. Overexpression of HDACs is found in some types of tumors and predicts poor prognosis. Five HDAC inhibitors are approved for the treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and multiple myeloma. Treatment with HDAC inhibitors regulates gene expression with increased acetylated histones with unconfirmed connection with therapy. Apoptosis is a key mechanism by which HDAC inhibitors selectively kill cancer cells, probably due to acetylation of non-histone proteins. Ku70 is a protein that repairs DNA breaks and stabilizes anti-apoptotic protein c-FLIP and proapoptotic protein Bax, which is regulated by acetylation. HDAC inhibitors induce Ku70 acetylation with repressed c-FLIP and activated Bax in cancer cells. Current studies indicate that Ku70 is a potential target of HDAC inhibitors and plays an important role during the induction of apoptosis.

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“…This PARP acetylation was associated with increased binding and subsequent trapping to DSBs with the use of PARP inhibitors and a resultant increase in cell death [43]. Additionally, it has been shown that the triple combination of HDAC, PARP, and DNMT inhibitors produced enhanced synergy in leukemia cells, furthering the use of PARP inhibitors in this disease [44].…”

Section: Combining Parp Inhibitors With Other Agents To Enhance Parp mentioning

confidence: 99%

Partnering with PARP inhibitors in acute myeloid leukemia with FLT3-ITD

Dellomo

Rassool

2019

Cancer Letters

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Internal tandem duplications within the juxtamembrane domain of fms-like tyrosine kinase 3 (FLT3-ITD) occur in acute myeloid leukemia (AML) cells of 20-25% of patients and are associated with poor treatment outcomes. FLT3 inhibitors have been developed, but have had limited clinical efficacy due to development of resistance, highlighting the need for better understanding of the function of FLT3-ITD and how to target it more effectively using novel combination strategies. Poly (ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in cancers with impaired homologous recombination (HR) due to BRCA mutations, but PARP inhibitor efficacy has not been fully explored in BRCA-proficient cancers, including AML. Recent research has connected inhibition of FLT3-ITD signaling to downregulation of numerous DNA repair proteins, including those involved in HR, and the novel combination with PARP inhibitors induces synthetic lethality in AML. Additionally, PARP inhibitor therapy may also target the highly error-prone alternative non-homologous end-joining (ALT NHEJ) DNA repair pathway in which PARP participates, thereby decreasing genomic instability and development of therapy resistance. Therefore, PARP inhibitors may be attractive therapeutic agents in combination with FLT3 inhibitors in FLT3-ITD AML.

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Combination of a hypomethylating agent and inhibitors of PARP and HDAC traps PARP1 and DNMT1 to chromatin, acetylates DNA repair proteins, down-regulates NuRD and induces apoptosis in human leukemia and lymphoma cells

Cited by 41 publications

References 41 publications

Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma

Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma

Apoptosis Induction byHistone Deacetylase Inhibitors in Cancer Cells: Role of Ku70

Partnering with PARP inhibitors in acute myeloid leukemia with FLT3-ITD

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