Inhibition of DNA damage response pathway using combination of DDR pathway inhibitors and radiation in treatment of acute lymphoblastic leukemia cells

An alarming increase in acute lymphoblastic leukemia cases among children and adults has attracted the attention of researchers to discover new therapeutic strategies with a better prognosis. In cancer cells, the DNA damage response (DDR) pathway elements have been recognized to protect tumor cells from various stresses and cause tumor progression; targeting these DDR members is an attractive strategy for treatment of cancers. The inhibition of the DDR pathway in cancer cells for the treatment of cancers has recently been introduced. Hence, effective treatment strategies are needed for this purpose. Chemotherapy in combination with radiotherapy is considered a potential therapeutic strategy for acute leukemia. This review aims to assess the synergistic effects of these inhibitors with irradiation for the treatment of leukemia.

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Novel SIRT1 Agonists, SRT501 and SRT2183, Induce Expression of DNA Repair Genes and Apoptosis of Ph− Acute Lymphoblastic Leukemia Cells Alone and in Combination with the HDAC Inhibitor LBH589..

Blood ◽

10.1182/blood.v114.22.3083.3083 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3083-3083

Author(s):

Anna Scuto ◽

Mark Kirschbaum ◽

Jennifer M Cermak ◽

Peter Atadja ◽

Richard Jove

Keyword(s):

Dna Damage ◽

Acute Lymphoblastic Leukemia ◽

Histone Deacetylase ◽

Dna Damage Response ◽

Histone Deacetylase Inhibitors ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Growth Arrest ◽

Mrna Levels ◽

Damage Response

Abstract Abstract 3083 Poster Board III-20 Histone Deacetylase Inhibitors (HDACi) such as LBH589, which inhibit the zinc containing catalytic domain of HDAC of classes I, II, and IV, demonstrate activity against various malignancies, particularly lymphoid malignancies. SIRT1 is an NAD+ dependent class III histone deacetylase, which deacetylates histones as well as non-histone proteins and is not affected directly by HDACi such as LBH589. It remains controversial whether inhibition of SIRT1 or its activation is more efficacious in anticancer therapy. We have studied the activity of two novel SIRT1 activators, SRT501 and SRT2183, in Philadelphia chromosome negative acute lymphoblastic leukemia (ALL) cell lines. Both pre B (NALM-6, Reh) and T cell (MOLT-4) ALL lines were treated with either SRT501 or SRT2183, as well as in combination with LBH589 and evaluated for biological and gene expression responses. SRT501 induced growth arrest and apoptosis at doses ranging from 10-100 uM, with even the lowest doses inhibiting growth at 72 hours. SRT2183 is much more potent, with growth arrest and apoptosis induced at doses ranging from 1-20 uM. PCR array analysis revealed that SRT2183 treatment leads to increased mRNA levels of pro-apoptosis, growth arrest, and DNA damage response genes. We have previously demonstrated that the activity of LBH589 is mediated in part through upregulation or acetylation of proteins involved in the DNA damage response pathways. Quantitative real-time PCR confirms that the combination of LBH589 with SRT2183 leads to significantly higher expression of GADD45A and GADD45G than either agent alone. The combination of LBH589 plus SRT2183 showed enhanced inhibition of c-Myc protein levels, phosphorylation of H2A.X, and interestingly, increased acetylation of p53 (acetylation of p53 was not seen with SRT2183 alone). In summary, the novel SIRT1 activators SRT501 and SRT2183 show growth inhibitory and pro-apoptotic activity in Ph- ALL alone and enhanced activity in combination with LBH589. Clinical studies of these agents, particularly in combination with HDACi are warranted. Disclosures Kirschbaum: Novartis: Consultancy. Cermak:Sirtris: Employment. Atadja:Novartis: Employment.

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Selective Induction of Necrotic Cell Death in Cancer Cells by β-Lapachone through Activation of DNA Damage Response Pathway

Cell Cycle ◽

10.4161/cc.5.17.3312 ◽

2006 ◽

Vol 5 (17) ◽

pp. 2029-2035 ◽

Cited By ~ 25

Author(s):

Xiangao Sun ◽

Youzhi Li ◽

Wei Li ◽

Bin Zhang ◽

A.J. Wang ◽

...

Keyword(s):

Dna Damage ◽

Cell Death ◽

Cancer Cells ◽

Dna Damage Response ◽

Necrotic Cell Death ◽

Necrotic Cell ◽

Damage Response ◽

Dna Damage Response Pathway

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LncRNAs downregulated in childhood acute lymphoblastic leukemia modulate apoptosis, cell migration, and DNA damage response

Oncotarget ◽

10.18632/oncotarget.20817 ◽

2017 ◽

Vol 8 (46) ◽

pp. 80645-80650 ◽

Cited By ~ 14

Author(s):

Romain Gioia ◽

Simon Drouin ◽

Manon Ouimet ◽

Maxime Caron ◽

Pascal St-Onge ◽

...

Keyword(s):

Dna Damage ◽

Cell Migration ◽

Acute Lymphoblastic Leukemia ◽

Dna Damage Response ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Damage Response

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Cytotoxic mechanism of novel compound jiangxienone from Cordyceps jiangxiensis against cancer cells involving DNA damage response pathway

Process Biochemistry ◽

10.1016/j.procbio.2014.01.027 ◽

2014 ◽

Vol 49 (4) ◽

pp. 697-705 ◽

Cited By ~ 2

Author(s):

Yu-Hong Lü ◽

Wei-Dong Pan ◽

Jian-Hui Xiao ◽

Zhong-Hua Sun ◽

Jian-Jiang Zhong

Keyword(s):

Dna Damage ◽

Cancer Cells ◽

Dna Damage Response ◽

Damage Response ◽

Cytotoxic Mechanism ◽

Dna Damage Response Pathway

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Growth Factor Independence 1 Antagonizes a p53-Induced DNA Damage Response Pathway in Lymphoblastic Leukemia

Cancer Cell ◽

10.1016/j.ccr.2013.01.011 ◽

2013 ◽

Vol 23 (2) ◽

pp. 200-214 ◽

Cited By ~ 47

Author(s):

Cyrus Khandanpour ◽

James D. Phelan ◽

Lothar Vassen ◽

Judith Schütte ◽

Riyan Chen ◽

...

Keyword(s):

Dna Damage ◽

Growth Factor ◽

Dna Damage Response ◽

Lymphoblastic Leukemia ◽

Damage Response ◽

Dna Damage Response Pathway

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The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph− acute lymphoblastic leukemia cells

Blood ◽

10.1182/blood-2007-10-117762 ◽

2008 ◽

Vol 111 (10) ◽

pp. 5093-5100 ◽

Cited By ~ 92

Author(s):

Anna Scuto ◽

Mark Kirschbaum ◽

Claudia Kowolik ◽

Leo Kretzner ◽

Agnes Juhasz ◽

...

Keyword(s):

Dna Damage ◽

Acute Lymphoblastic Leukemia ◽

Dna Damage Response ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Growth Arrest ◽

Clinical Activity ◽

Mrna Levels ◽

Damage Response ◽

Potent Growth

Abstract We investigated the mechanism of action of LBH589, a novel broad-spectrum HDAC inhibitor belonging to the hydroxamate class, in Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL). Two model human Ph− ALL cell lines (T-cell MOLT-4 and pre–B-cell Reh) were treated with LBH589 and evaluated for biologic and gene expression responses. Low nanomolar concentrations (IC50: 5-20 nM) of LBH589 induced cell-cycle arrest, apoptosis, and histone (H3K9 and H4K8) hyperacetylation. LBH589 treatment increased mRNA levels of proapoptosis, growth arrest, and DNA damage repair genes including FANCG, FOXO3A, GADD45A, GADD45B, and GADD45G. The most dramatically expressed gene (up to 45-fold induction) observed after treatment with LBH589 is GADD45G. LBH589 treatment was associated with increased histone acetylation at the GADD45G promoter and phosphorylation of histone H2A.X. Furthermore, treatment with LBH589 was active against cultured primary Ph− ALL cells, including those from a relapsed patient, inducing loss of cell viability (up to 70%) and induction of GADD45G mRNA expression (up to 35-fold). Thus, LBH589 possesses potent growth inhibitory activity against including Ph− ALL cells associated with up-regulation of genes critical for DNA damage response and growth arrest. These findings provide a rationale for exploring the clinical activity of LBH589 in the treatment of patients with Ph− ALL.

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