Potentiation of reactive oxygen species is a marker for synergistic cytotoxicity of MS-275 and 5-azacytidine in leukemic cells

Gao, Shan; Mobley, Aaron K.; Miller, Claudia P.; Boklan, Jessica; Chandra, Joya

doi:10.1016/j.leukres.2007.09.007

Cited by 52 publications

(37 citation statements)

References 31 publications

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“…Apoptotic mechanism of SAHA has been explained to initiate cell death via mitochondria-mediated death pathway which is characterized by cytochrome c release and ROS generation, but does not require the activation of key caspases such as caspase-8 or caspase-3. 41,42 We have observed similar findings for SAHA and our results suggest that SAHA-mediated ROS formation plays an important role in CML cells. In our study, use of SAHA increased 43 showed that combined treatment of myeloma cells with bortezomib and HDI triggers PARP degradation and release of cytochrome c. Besides, SAHA-related cytochrome c release was increased in combination thus initiating apoptosis.…”

Section: Analysis Of Apoptotic Protein Expression By Western Blotsupporting

confidence: 85%

Synergistic Effects of Methotrexate and Suberoylanilide Hydroxamic Acid in Triggering Apoptosis of Chronic Myeloid Leukemia Cells

2015

UHOD

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In this study, we have investigated the effects of suberoylanilide hydroxamic acid (SAHA) against chronic myeloid leukemia (CML) cells in combination studies with methotrexate (MTX), which is a dihydrofolate reductase inhibitor used in combination therapy with other agents or alone. Combination of synergistic ratios of MTX and SAHA led to apoptotic cell death of CML cells via PARP cleavage, cytochrome c release and ROS increase in vitro. We suggest that combination of MTX and SAHA may minimize the toxicity and side effects of SAHA treatment, thus providing lower amounts of each drug in CML treatment.

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Section: Analysis Of Apoptotic Protein Expression By Western Blotsupporting

confidence: 85%

Synergistic Effects of Methotrexate and Suberoylanilide Hydroxamic Acid in Triggering Apoptosis of Chronic Myeloid Leukemia Cells

2015

UHOD

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“…However, this was purely speculation, and no experiments to address this possibility have been conducted. Building on those observations, both azacytidine and 5-aza-2-deoxycytidine are seen to cause increased ROS alone or in combination with other epigenetically targeted agents, such as HDAC inhibitors (31). Antioxidants able to stem this increase in ROS are those that bolster levels of GSH, suggesting that GSH depletion plays a role in the mechanism of action of these agents.…”

Section: Fig 5 Proteasome Inhibitors Can Promote An Antioxidant Resmentioning

confidence: 90%

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

Chandra

2009

Antioxidants & Redox Signaling

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The past decade has seen an exponential increase in the number of cancer therapies with defined molecular targets. Interestingly, many of these new agents are also documented to raise levels of intracellular reactive oxygen species (ROS) in addition to inhibiting a biochemical target. In most cases, the exact link between the primary target of the drug and effects on cellular redox status is unknown. However, it is important to understand the role of oxidative stress in promoting cytotoxicity by these agents, because the design of multiregimen strategies could conceivably build on these redox alterations. Also, drug resistance mediated by antioxidant defenses could potentially be anticipated and circumvented with improved knowledge of the redoxrelated effects of these targeted agents. Given the large number of targeted chemotherapies, in this review, we focus on selected agents that have shown promise in hematologic malignancies: proteasome inhibitors, histone deacetylase inhibitors, Bcl-2-targeted agents, and a kinase inhibitor called adaphostin. Despite structural differences within classes of these compounds, a commonality of causing increased oxidative stress exists, which contributes to induction of cell death. Antioxid. Redox Signal. 11, 1123-1137.

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“…Inhibition of caspases does not block HDAC inhibitor induced cell death. This means that HDAC inhibitors also induce non-caspase types of cancer cell death 47,48 . Two mechanisms responsible for induction of oxidative stress by HDAC inhibitors may be damage to mitochondria and modulation of cellular antioxidants 49 .…”

Section: Histone Deacetylase Inhibitors and Apoptosismentioning

confidence: 99%

Histone deacetylase inhibitors in cancer therapy. A review

Hraběta¹,

Stiborová²,

Adam³

et al. 2014

BIOMED PAP

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a Background. Despite recent success toward discovery of more effective anticancer drugs, chemoresistance remains a major cause of treatment failure. There is emerging evidence that epigenetics plays a key role in the development of the resistance. Epigenetic regulators such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) play an important role in gene expression. The latter are found to be commonly linked with many types of cancers and influence cancer development. Overall, histone acetylation is being investigated as a therapeutic target because of its importance in regulating gene expression. This review summarizes mechanisms of the anticancer effects of histone deacetylase (HDAC) inhibitors and the results of clinical studies. Results. Different HDAC inhibitors induce cancer cell death by different mechanisms that include changes in gene expression and alteration of both histone and non-histone proteins. Enhanced histone acetylation in tumors results in modification of expression of genes involved in cell signaling. Inhibition of HDACs causes changed expression in 2-10 % of genes involved in important biological processes. The results of experiments and clinical studies demonstrate that combination of HDAC inhibitors with some anticancer drugs have synergistic or additive effects. Conclusions. Even though many biological effects of HDAC inhibitors have been found, most of the mechanisms of their action remain unclear. In addition, their use in combination with other drugs and the combination regime need to be investigated. The discovery of predictive factors is also necessary. Finally, a key question is whether the pan-HDAC inhibitors or the selective inhibitors will be more efficient for different types of cancers.

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Potentiation of reactive oxygen species is a marker for synergistic cytotoxicity of MS-275 and 5-azacytidine in leukemic cells

Cited by 52 publications

References 31 publications

Synergistic Effects of Methotrexate and Suberoylanilide Hydroxamic Acid in Triggering Apoptosis of Chronic Myeloid Leukemia Cells

Synergistic Effects of Methotrexate and Suberoylanilide Hydroxamic Acid in Triggering Apoptosis of Chronic Myeloid Leukemia Cells

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

Histone deacetylase inhibitors in cancer therapy. A review

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