The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity

Tarasenko, Nataly; Kessler‐Icekson, Gania; Boer, P.; Inbal, Aida; Schlesinger, Hadassa; Phillips, Don R.; Cutts, Suzanne M.; Nudelman, Abraham; Rephaeli, Ada

doi:10.1007/s10637-010-9542-z

Cited by 34 publications

(30 citation statements)

References 40 publications

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“…Our group previously demonstrated the protective effect of AN-7 against Dox-toxicity in cardiomyocytes and astrocytes and AN-7 augmentation of Dox's anticancer activity against breast carcinoma and glioblastoma cells in vitro [12], [15]. The aim of the present study was to substantiate our earlier findings in vivo and to investigate the underlying cellular and molecular modifications responsible for this disparity.…”

Section: Discussionsupporting

confidence: 54%

“…Previously, we have shown that AN-7 synergistically increased Dox cytotoxicity against 4T1 cells, and conversely, it protected cardiomyocytes against Dox toxicity [12]. In an attempt to understand the basis for this disparity, we examined the manner by which AN-7, Dox and AN-7+Dox affect the total cellular activity of HDACs classes I and II in these cancerous and non-cancerous cells.…”

Section: Resultsmentioning

confidence: 95%

“…Previously, we have shown that the viability of cardiofibroblasts was dramatically repressed by AN-7+Dox, suggesting that in the heart, AN-7 may attenuate Dox-induced fibrosis [12]. Heart fibrosis is a classical feature of tissue remodeling in a response to a variety of pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

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Disparate Impact of Butyroyloxymethyl Diethylphosphate (AN-7), a Histone Deacetylase Inhibitor, and Doxorubicin in Mice Bearing a Mammary Tumor

et al. 2012

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The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) synergizes the cytotoxic effect of doxorubicin (Dox) and anti-HER2 on mammary carcinoma cells while protecting normal cells against their insults. This study investigated the concomitant changes occurring in heart tissue and tumors of mice bearing a subcutaneous 4T1 mammary tumor following treatment with AN-7, Dox, or their combination. Dox or AN-7 alone led to inhibition of both tumor growth and lung metastases, whereas their combination significantly increased their anticancer efficacy and attenuated Dox- toxicity. Molecular analysis revealed that treatment with Dox, AN-7, and to a greater degree, AN-7 together with Dox increased tumor levels of γH2AX, the marker for DNA double-strand breaks and decreased the expression of Rad51, a protein needed for DNA repair. These events culminated in increased apoptosis, manifested by the appearance of cytochrome-c in the cytosol. In the myocardium, Dox-induced cardiomyopathy was associated with an increase in γH2AX expression and a reduction in Rad51 and MRE11 expression and increased apoptosis. The addition of AN-7 to the Dox treatment protected the heart from Dox insults as was manifested by a decrease in γH2AX levels, an increase in Rad51 and MRE11 expression, and a diminution of cytochrome-c release. Tumor fibrosis was high in untreated mice but diminished in Dox- and AN-7-treated mice and was almost abrogated in AN-7+Dox-treated mice. By contrast, in the myocardium, Dox alone induced a dramatic increase in fibrosis, and AN7+Dox attenuated it. The high expression levels of c-Kit, Ki-67, c-Myc, lo-FGF, and VEGF in 4T1 tumors were significantly reduced by Dox or AN-7 and further attenuated by AN-7+Dox. In the myocardium, Dox suppressed these markers, whereas AN-7+Dox restored their expression. In conclusion, the combination of AN-7 and Dox results in two beneficial effects, improved anticancer efficacy and cardioprotection.

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Section: Discussionsupporting

confidence: 54%

Section: Resultsmentioning

confidence: 95%

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Disparate Impact of Butyroyloxymethyl Diethylphosphate (AN-7), a Histone Deacetylase Inhibitor, and Doxorubicin in Mice Bearing a Mammary Tumor

et al. 2012

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“…7). Further evaluation of the mechanisms engaged in ADs-mediated neuroprotection against Dox toxicity would be very important from the clinical point of view since glia cell damage occurs during chemotherapy and concomitantly with neuronal cell damage participate in neurocognitive impairments observed in patients after long-term chemotherapy (Bigotte and Olsson 1983; Moriuchi et al 1996; O’Farrell et al 2013; Tarasenko et al 2012). Regarding the protective effects of Tian in glia cells, it has been shown that Tian (10–100 μM) attenuated the gp120-evoked cell death in glia cells and this effect was connected with attenuation of caspase-3 activity, DNA fragmentation and the influence of this drug on the expression and activity of glutamine synthase (GS), transcription factor NFκB, and nitric oxide system (NO, cNOS, iNOS) (Janda et al 2011).…”

Section: Discussionmentioning

confidence: 99%

The Predominant Protective Effect of Tianeptine Over Other Antidepressants in Models of Neuronal Apoptosis: The Effect Blocked by Inhibitors of MAPK/ERK1/2 and PI3-K/Akt Pathways

2013

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Tianeptine (Tian) possesses neuroprotective potential, however, little is known about the effect of this drug in models of neuronal apoptosis. In the present study, we aimed (1) to compare the neuroprotective capacities of some antidepressants (ADs) in the models of staurosporine (St)- and doxorubicin (Dox)-evoked cell death, activating the intracellular and the extracellular apoptotic pathway, respectively; (2) to identify the Tian-modulated steps underlying its neuroprotective action; (3) to test the effect of various ADs against Dox-evoked cell damage in glia cells. Primary neuronal and glia cell cultures and retinoic acid-differentiated human neuroblastoma SH-SY5Y (RA-SH-SY5Y) cells were co-treated with imipramine, fluoxetine, citalopram, reboxetine, mirtazapine or Tian and St or Dox. The data showed the predominant neuroprotective effect of Tian over other tested ADs against St- and Dox-induced cell damage in primary neurons and in RA-SH-SY5Y cells. This effect was shown to be caspase-3-independent but connected with attenuation of DNA fragmentation. Moreover, neuroprotection elicited by Tian was blocked by pharmacological inhibitors of MAPK/ERK1/2 and PI3-K/Akt signaling pathways as well by inhibitor of necroptosis, necrostatin-1. Interestingly, the protective effects of all tested ADs were demonstrated in primary glia cells against the Dox-evoked cell damage. The obtained data suggests the glial cells as a common target for protective action of various ADs whereas in relation to neuronal cells only Tian possesses such properties, at least against St- and Dox-induced cell damage. Moreover, this neuroprotective effect of Tian is caspase-3-independent and engages the regulation of survival pathways (MAPK/ERK1/2 and PI3-K/Akt).Electronic supplementary materialThe online version of this article (doi:10.1007/s12640-013-9430-3) contains supplementary material, which is available to authorized users.

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“…Arterial smooth muscle cells from mice overexpressing a nonfunctional form of Nox4 showed decreased TSP1 mRNA and protein expression (275), suggesting that Nox4 is a proximate driver of TSP1 expression. Fibroblasts treated with doxorubicin displayed increased ROS levels and TSP1 protein expression (269).…”

Section: Tsp1 and Ros Signaling In Vivomentioning

confidence: 96%

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Roberts

Kaur

Isenberg

2017

Antioxidants & Redox Signaling

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Significance: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Critical Issues: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Future Directions: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

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The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity

Cited by 34 publications

References 40 publications

Disparate Impact of Butyroyloxymethyl Diethylphosphate (AN-7), a Histone Deacetylase Inhibitor, and Doxorubicin in Mice Bearing a Mammary Tumor

Disparate Impact of Butyroyloxymethyl Diethylphosphate (AN-7), a Histone Deacetylase Inhibitor, and Doxorubicin in Mice Bearing a Mammary Tumor

The Predominant Protective Effect of Tianeptine Over Other Antidepressants in Models of Neuronal Apoptosis: The Effect Blocked by Inhibitors of MAPK/ERK1/2 and PI3-K/Akt Pathways

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

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