API

Relationship: 1716

Title

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Histone deacetylase inhibition leads to Apoptosis

Upstream event

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Histone deacetylase inhibition

Downstream event

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Apoptosis

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Histone deacetylase inhibition leading to testicular toxicity non-adjacent High High

Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
Not Otherwise Specified High

Key Event Relationship Description

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HDAC inhibition leads to cell death through the apoptotic pathways [Falkenberg, 2014]. Intrinsic apoptosis pathway requires BH3-only proteins, and BCL-2 protein overexpression inhibits apoptosis [Falkenberg, 2014].

Evidence Supporting this KER

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Biological Plausibility

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HDAC inhibition in cancer results in apoptosis with the up-regulation of pro-apoptotic B cell lymphoma 2 (BCL-2) family genes and down- regulation of pro-survival BCL-2 genes [Falkenberg, 2014]. The antitumor effect of HDAC inhibition includes cell death and apoptosis [Falkenberg, 2014].

Empirical Evidence

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  • HDAC-deficient mouse embryonic stem (ES) cells showed reduced proliferation rates with up-regulation of cyclin-dependent kinase inhibitors p21 and p27 [Lagger, 2002]. HDAC-null embryoid bodies showed a reduced inner cell mass and reduced colony formation [Lagger, 2002].
  • HDAC inhibition by suberoylanilide hydroxamic acid (SAHA) inhibited proliferation of normal human dermal fibroblasts (NHDF) [Glaser, 2003].
  • MAA-induced spermatocyte death is associated with histone acetylation increase [Wade, 2008].
  • The HDAC inhibition induced p21 up-regulation, histone acetylation increase, and apoptosis markers such as BAK overexpression and suppression of phosphorylated AKT [Henderson, 2016]. AR-42 inhibited the expression of BCL-XL, an anti-apoptotic molecule in AsPC-1 tumor homogenates collected after 21 days of treatment [Henderson, 2016]. Oral administration of AR-42, a HDAC inhibitor, at 50 mg/kg in human pancreatic cancer cell AsPC-1 xenograft and KPfl/flC models resulted in the suppression of tumor [Henderson, 2016].

Uncertainties and Inconsistencies

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Methoxyacetic acid (MAA), a HDAC inhibitor, induced cell cycle arrest, apoptosis, leading to suppression of human prostate cancer cell growth [Parajuli, 2014]. It is not fully elucidated whether MAA-induced apoptosis is involved in p53/p63/p73 pathway [Parajuli, 2014].

Quantitative Understanding of the Linkage

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MAA (5 mM) induced apoptosis in prostate cancer cell lines, LNCaP, C4-2B, PC-3 and DU-145, in which apoptotic nucleosomes were calculated as absorbance at 405 nm – absorbance at 490 nm [Parajuli, 2014].

Response-response Relationship

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Time-scale

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MAA (5 mM) decreased protein expression of BIRC2 and activated caspases 7 and 3 within 72 hrs [Parajuli, 2014].

Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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AR-42 inhibited proliferation of human pancreatic cancer cells (Homo sapiens) [Henderson, 2016]. SAHA inhibited proliferation of NHDF (Homo sapiens) [Glaser, 2003]. MAA induced apoptosis in human prostate cancer cell lines (Homo sapiens) [Parajuli, 2014]. HDAC-deficient mouse ES cells showed decrease in proliferation (Mus musculus) [Lagger, 2002].

References

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Falkenberg KJ and Johnstone RW. (2014) Histone deacetylases and their inhibitors in cancer, neurological disease and immune disorders. Nat Rev Drug Discov 13:673-691

Lagger G et al. (2002) Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J 21:2672-2681

Glaser KB et al. (2003) Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2:151-163

Wade MG et al. (2008) Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats. Biol Reprod 78:822-831

Henderson SE et al. (2016) Suppression of tumor growth and muscle wasting in a transgenic mouse model of pancreatic cancer by the novel histone deacetylase inhibitor AR-42. Neoplasia 18:765-774

Parajuli KR et al. (2014) Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis. Am J Clin Exp Urol 2:300-312