Upstream eventHistone deacetylase inhibition
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leading to testicular toxicity||non-adjacent||High||High|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
Life Stage Applicability
|Not Otherwise Specified||High|
Key Event Relationship Description
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
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].
- 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
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
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].
MAA (5 mM) decreased protein expression of BIRC2 and activated caspases 7 and 3 within 72 hrs [Parajuli, 2014].
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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].
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