In Vivo Effects of Histone‐Deacetylase Inhibitor Trichostatin‐A on Murine Spermatogenesis

Fenic, Irina; Sonnack, Violetta; Failing, Klaus; Bergmann, Martin; Steger, Klaus

doi:10.1002/j.1939-4640.2004.tb02859.x

Cited by 106 publications

(88 citation statements)

References 29 publications

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“…Although testicular toxicities are common adverse side effects of cancer therapy (44), to our knowledge, investigators have not previously reported testicular pathology as a consequence of HDAC inhibitor treatment in preclinical models of human cancer. A single study examining the antifertility effect of trichostatin A in mice reported a completely reversible impairment of spermatogenesis resulting from increased apoptosis of spermatocytes (45). Although we do not know the cellular target mediating this toxicity of (S)-HDAC-42, the lack of pathologic changes in the pituitary and accessory sex organs suggests a primary testicular toxicity.…”

Section: Discussionmentioning

confidence: 88%

Antitumor Effects of a Novel Phenylbutyrate-Based Histone Deacetylase Inhibitor, (S)-HDAC-42, in Prostate Cancer

Kulp

Chen

Wang

et al. 2006

Clinical Cancer Research

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Purpose: To assess the antitumor effects of a novel phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, (S)-HDAC-42, vis-a' -vis suberoylanilide hydroxamic acid (SAHA) in in vitro and in vivo models of human prostate cancer. Experimental Design:The in vitro effects of (S)-HDAC-42 and SAHA were evaluated in PC-3, DU-145, or LNCaP human prostate cancer cell lines. Cell viability, apoptosis, and indicators of HDAC inhibition were assessed. Effects on Akt and members of the Bcl-2 and inhibitor of apoptosis protein families were determined by immunoblotting. Immunocompromised mice bearing established s.c. PC-3 xenograft tumors were treated orally with (S)-HDAC-42 (50 mg/kg q.o.d. or 25 mg/kg q.d.) or SAHA (50 mg/kg q.d.) for 28 days. In vivo end points included tumor volumes and intratumoral changes in histone acetylation, phospho-Akt status, and protein levels of Bcl-xL and survivin. Results: (S)-HDAC-42 was more potent than SAHA in suppressing the viability of all cell lines evaluated with submicromolar IC 50 values. Relative to SAHA, (S)-HDAC-42 exhibited distinctly superior apoptogenic potency, and caused markedly greater decreases in phospho-Akt, Bcl-xL, and survivin in PC-3 cells. The growth of PC-3 tumor xenografts was suppressed by 52% and 67% after treatment with (S)-HDAC-42 at 25 and 50 mg/kg, respectively, whereas SAHA at 50 mg/kg suppressed growth by 31%. Intratumoral levels of phospho-Akt and Bcl-xL were markedly reduced in (S)-HDAC-42-treated mice, in contrast to mice treated with SAHA. Conclusions: (S)-HDAC-42 is a potent orally bioavailable inhibitor of HDAC, as well as targets regulating multiple aspects of cancer cell survival, which might have clinical value in prostate cancer chemotherapy and warrants further investigation in this regard.

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Section: Discussionmentioning

confidence: 88%

Antitumor Effects of a Novel Phenylbutyrate-Based Histone Deacetylase Inhibitor, (S)-HDAC-42, in Prostate Cancer

Kulp

Chen

Wang

et al. 2006

Clinical Cancer Research

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“…Furthermore, withdrawal of TSA led to complete regeneration of the seminiferous epithelium in fertility assays [74]. On the contrary, apoptosis of both spermatocytes and spermatids significantly increased with increasing TSA doses, suggesting for an inhibitory role of TSA mainly on meiosis but not mitosis [75,76]. During spermatogenesis, methylation of H3K and H4K histone tails is regulated by histone methyltransferases (HTM) and histone demethylases (HDM) [77,78].…”

Section: Role Of Histone Modifications In Male Infertilitymentioning

confidence: 99%

The role of epigenetics in idiopathic male infertility

Güneş

Arslan

Hekim

et al. 2016

J Assist Reprod Genet

106

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Infertility is a complex disorder with multiple genetic and environmental causes. Although some specific mutations have been identified, other factors responsible for sperm defects remain largely unknown. Despite considerable efforts to identify the pathophysiology of the disease, we cannot explain the underlying mechanisms of approximately half of infertility cases. This study reviews current data on epigenetic regulation and idiopathic male infertility. Recent data have shown an association between epigenetic modifications and idiopathic infertility. In this regard, epigenetics has emerged as one of the promising research areas in understanding male infertility. Many studies have indicated that epigenetic modifications, including DNA methylation in imprinted and developmental genes, histone tail modifications and short non-coding RNAs in spermatozoa may have a role in idiopathic male infertility.

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“…In mammals, reduced levels of histone H4 hyperacetylation correlates with impaired fertility (95,98).…”

Section: The Effects Of Bacterial Infection On Sperm Chromatin Condenmentioning

confidence: 99%

The Impact of Bacterial Infections on Human Spermatozoa

Zeyad¹,

Amor²,

Hammadeh³

2017

International Journal of Women’s Health and Reproduction Scienc

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In Vivo Effects of Histone‐Deacetylase Inhibitor Trichostatin‐A on Murine Spermatogenesis

Cited by 106 publications

References 29 publications

Antitumor Effects of a Novel Phenylbutyrate-Based Histone Deacetylase Inhibitor, (S)-HDAC-42, in Prostate Cancer

Antitumor Effects of a Novel Phenylbutyrate-Based Histone Deacetylase Inhibitor, (S)-HDAC-42, in Prostate Cancer

The role of epigenetics in idiopathic male infertility

The Impact of Bacterial Infections on Human Spermatozoa

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