Vorinostat Induces Reactive Oxygen Species and DNA Damage in Acute Myeloid Leukemia Cells

Petruccelli, Luca A.; Dupéré-Richér, Daphne; Pettersson, Filippa; Retrouvey, Hélène; Skoulikas, Sophia; Miller, Wilson H.

doi:10.1371/journal.pone.0020987

Cited by 120 publications

(94 citation statements)

References 49 publications

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“…Results of this study showed that vorinostat, the histone deacetylase inhibitor, is genotoxic to human lymphocytes, as indicated by the increased frequencies of SCEs and CAs in vorinostat-treated cells. This is consistent with previous studies showing that vorinostat induces oxidative DNA damage through the course of its action (Namdar et al 2010;Petruccelli et al 2011;Lee et al 2010), though it was shown to be more effective on cells with lower oxidative stress status or cells pre-treated with an antioxidant (Basu et al 2011).…”

Section: Resultssupporting

confidence: 92%

“…Tempol (Sigma-Aldrich, St. Louis, MO, USA) was prepared in a similar way to that of vorinostat and was used in a final concentration of 10 lM. Tempol was added at the time of culture, while vorinostat was added 16 h prior to harvesting (Petruccelli et al 2011;Lee et al 2010). To evaluate the effect of vorinostat on DNA and how this effect is modulated by tempol, four groups were used: control non-treated (Control), tempol-treated (Temp), vorinostat-treated (Vori), and tempol and vorinostat treated (Temp ?…”

Section: Lymphocytes Culture and Drug Treatmentmentioning

confidence: 99%

“…In addition, studies have shown that vorinostat induces DNA damage, which is proposed to be due to the generation of oxidative lesions (Namdar et al 2010;Petruccelli et al 2011;Lee et al 2010). The increase in DNA damage caused by several anticancer drugs has been shown to increase the risk of developing secondary cancer (Madeya 1996;Ezoe 2012).…”

Section: Introductionmentioning

confidence: 99%

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Tempol prevents genotoxicity induced by vorinostat: role of oxidative DNA damage

et al. 2013

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Vorinostat is a member of histone deacetylase inhibitors, which represents a new class of anticancer agents for the treatment of solid and hematological malignancies. Studies have shown that these drugs induce DNA damage in blood lymphocytes, which is proposed to be due to the generation of oxidative lesions. The increase in DNA damage is sometimes associated with risk of developing secondary cancer. Thus, finding a treatment that limits DNA damage caused by anticancer drugs would be beneficial. Tempol is a potent antioxidant that was shown to prevent DNA damage induced by radiation. In this study, we aimed to investigate the harmful effects of vorinostat on DNA damage, and the possible protective effects of tempol against this damage. For that, the spontaneous frequency of sister chromatid exchanges (SCEs), chromosomal aberrations (CAs), and 8-hydroxy-2-deoxy guanosine (8-OHdG) levels were measured in cultured human lymphocytes treated with vorinostat and/or tempol. The results showed that vorinostat significantly increases the frequency of SCEs, CAs and 8-OHdG levels in human lymphocytes as compared to control. These increases were normalized by the treatment of cells with tempol. In conclusion, vorinostat is genotoxic to lymphocytes, and this toxicity is reduced by tempol. Such results could set the stage for future studies investigating the possible usefulness of antioxidants co-treatment in preventing the genotoxicity of vorinostat when used as anticancer in human.

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Section: Resultssupporting

confidence: 92%

Section: Lymphocytes Culture and Drug Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tempol prevents genotoxicity induced by vorinostat: role of oxidative DNA damage

et al. 2013

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“…Disordered epigenetics within AML cells originally suggested that HDACi may be useful for treating AML (40,41). HDACi kill AML cell lines and patient samples in vitro (42)(43)(44). Yet, HDACi drugs have displayed only limited efficacy (12,45,46).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts

Kremer

Dudakovic

Hess

et al. 2015

Journal of Biological Chemistry

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Disrupting the protective signals provided by the bone marrow microenvironment will be critical for more effective combination drug therapies for acute myeloid leukemia (AML). Cells of the osteoblast lineage that reside in the endosteal niche have been implicated in promoting survival of AML cells. Here, we investigated how to prevent this protective interaction. We previously showed that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis of AML cells, unless the leukemic cells receive protective signals provided by differentiating osteoblasts (8, 10). We now identify a novel signaling pathway in differentiating osteoblasts that can be manipulated to disrupt the osteoblast-mediated protection of AML cells. Treating differentiating osteoblasts with histone deacetylase inhibitors (HDACi) abrogated their ability to protect co-cultured AML cells from SDF-1-induced apoptosis. HDACi prominently upregulated expression of the Nherf1 scaffold protein, which played a major role in preventing osteoblast-mediated protection of AML cells. Protein phosphatase-1␣ (PP1␣) was identified as a novel Nherf1 interacting protein that acts as the downstream mediator of this response by promoting nuclear localization of the TAZ transcriptional modulator. Moreover, independent activation of either PP1␣ or TAZ was sufficient to prevent osteoblast-mediated protection of AML cells even in the absence of HDACi. Together, these results indicate that HDACi target the AML microenvironment by enhancing activation of the Nherf1-PP1␣-TAZ pathway in osteoblasts. Selective drug targeting of this osteoblast signaling pathway may improve treatments of AML by rendering leukemic cells in the bone marrow more susceptible to apoptosis.For decades, research into drug treatments for acute myeloid leukemia (AML) 2 has focused on directly targeting AML cells for destruction. Even though complete remission rates have improved, relapse remains a problem in the majority of patients with this disease. The bone marrow microenvironment has gained attention as a protective environment that promotes survival of AML stem cells, despite the killing of the majority of AML cells by standard chemotherapeutics (1-5). The endosteum, the tissue between the bone marrow and ossified surface, has been particularly implicated as a protective niche because AML stem cells are localized to this region following chemotherapeutics (6, 7). Within the endosteal niche, cells of the osteoblast (bone-generating) lineage have been identified as critical mediators of AML cell survival in the bone marrow (4, 8). Transgenic mice expressing activated ␤-catenin specifically in osteoblasts develop myeloid malignancy, consistent with the idea that osteoblasts promote this disease (9). Unfortunately, the molecular mechanisms responsible for osteoblast-mediated protection of AML cells are incompletely understood. This lack of knowledge prevents effective therapeutic manipulation of the bone marrow microenvironment as a way to enhance targeting of AML cells within the bone marrow. We...

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“…Synergistic effects of ixazomib with a histone deacetylase inhibitor in AML cells expressing NPMc þ Single-agent SAHA (Vorinostat), a histone deacetylase (HDAC) inhibitor with modest single-agent antileukemic activity (21), has also been shown to induce ROS as a mode of cytotoxicity in AML models (22), with evidence for synergistic cytotoxicity in combination with bortezomib (23)(24)(25). We therefore asked whether SAHA in combination with ixazomib would augment superoxide induction and enhance cytotoxicity.…”

Section: Cytotoxicity Of Ixazomib For Primary Aml Cellsmentioning

confidence: 99%

Selective Toxicity of Investigational Ixazomib for Human Leukemia Cells Expressing Mutant Cytoplasmic NPM1: Role of Reactive Oxygen Species

Garcia

Huang

Medeiros

et al. 2016

Clinical Cancer Research

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Purpose: This study was performed to determine whether the investigational proteasome inhibitor ixazomib demonstrated selective antineoplastic activity against acute myelogenous leukemia cells expressing a mutated nucleophosmin-1 gene and to gain a better understanding of its mechanisms of action. Experimental Design: The cytotoxic effects of ixazomib treatment were analyzed in human acute myelogenous leukemia (AML) cell lines and primary AML samples expressing wild-type or mutated NPM1 (NPMc+). The potential roles of oxidative stress in mediating cytotoxic activity were determined using flow cytometry, enzyme-based assays, and Western blots. Results: Apoptosis induced by ixazomib was abrogated by knockdown of NPM1/NPMc+ expression using an inducible shRNA construct and enhanced by NPMc+ overexpression. Cytotoxicity was associated with superoxide generation and was reduced by the addition of the antioxidant N-acetylcysteine. AML cells expressing NPMc+ had significantly reduced levels of intracellular glutathione and NADPH associated with reduced antioxidant responses to drug treatment. Treatment of 3 patients with relapsed NPMc+ AML resulted in an antileukemic effect in 1 patient as demonstrated by a marked reduction of leukemic blasts in the peripheral blood. Efficacy was associated with superoxide generation, reduced glutathione levels, and reduced mRNA and protein expression of antioxidant effectors in responding cells. Conclusions: In this study, a direct association was observed between NPMc+ expression in AML, reduced antioxidant responses, and enhanced sensitivity to an oral proteasome inhibitor that induces oxidative stress. These data suggest that intracellular determinants of antioxidant responses may be good predictors of therapeutic response to ixazomib. Clin Cancer Res; 22(8); 1978–88. ©2015 AACR.

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Vorinostat Induces Reactive Oxygen Species and DNA Damage in Acute Myeloid Leukemia Cells

Cited by 120 publications

References 49 publications

Tempol prevents genotoxicity induced by vorinostat: role of oxidative DNA damage

Tempol prevents genotoxicity induced by vorinostat: role of oxidative DNA damage

Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts

Selective Toxicity of Investigational Ixazomib for Human Leukemia Cells Expressing Mutant Cytoplasmic NPM1: Role of Reactive Oxygen Species

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