Wednesday 17 January 2018

Histone deacetylase inhibitors (HDACi)

I find a lot of information that histone deacetylase inhibitors (Trichostatin A (TSA), Vorinostat, 7-ureido-N-hydroxyheptanamide derivative (CKD5)) have potent anti-cancer effects in glioblastoma.

2017 https://www.ncbi.nlm.nih.gov/pubmed/27852054
"Our results demonstrate that the novel HDACI CKD5 is a promising therapeutic candidate for glioblastoma."

2017 https://www.ncbi.nlm.nih.gov/pubmed/27766591
"We conclude that the combined administration of TSA and CCNU eradicates GBM cells with a higher efficacy than either drug alone, thereby opening a novel avenue for the treatment of GBM."

2015 https://www.ncbi.nlm.nih.gov/pubmed/25634603
"...these results indicate that trichostatin A (TSA) suppresses ESCC cell growth by inhibiting the activation of the PI3K/Akt and ERK1/2 pathways. TSA also promotes cell apoptosis through epigenetic regulation of the expression of apoptosis‑related protein."

2014 https://www.ncbi.nlm.nih.gov/pubmed/24464841
"Here, we investigate the effects of the HDACi trichostatin A (TSA) in U87 GBM cultures and tumorsphere-derived cells. These findings indicate that HDACis can inhibit proliferation, survival, and tumorsphere formation, and promote differentiation of U87 GBM cells, providing further evidence for the development of HDACis as potential therapeutics against GBM."

The results of clinical trials, however, did not give a good result:

Phase I/II Trial of Vorinostat Combined with Temozolomide and Radiation Therapy for Newly Diagnosed Glioblastoma: Final Results of Alliance N0874/ABTC 02.
2017 https://www.ncbi.nlm.nih.gov/pubmed/29016887

Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma.
2017 https://www.ncbi.nlm.nih.gov/pubmed/29133513

"Valproic acid has also recently been demonstrated to be a potent histone deacetylase inhibitor."
Many patients with glioblastoma take valproic acid (Depakote) against epileptic attacks. However, this has no effect on overall survival. Perhaps it is necessary to increase the dose or combination with something? I found that disulfiram increases the content of valproic acid in the blood.

And by the way, I can not find any medicine containing Trichostatin A.

3 comments:

  1. The only approved HDAC inhibitors, at least in the USA, are: vorinostat, romidepsin, belinostat, and panobinostat. Both vorinostat and panobinostat have been tested in GBM clinical trials, but haven't shown much additional benefit. As with many drugs developed for non central nervous system cancers, this could perhaps be a pharmacokinetic problem, with sufficient levels of the drug failing to penetrate the blood brain barrier.

    Trichostatin A is used only in preclinical research and has not even made it to the clinical trial stage.

    Valproic acid is actually a fairly weak HDAC inhibitor, with achievable free plasma levels (~200 micromolar) only reaching 20-30% of IC50 values for class one HDAC inhibition (0.7-1 millimolar).
    http://cancerres.aacrjournals.org/content/canres/64/3/1079.full.pdf

    The most impressive outcomes for a valproic acid trial for brain tumors, was a trial that added VPA during the 6 weeks of chemoradiation for newly diagnosed GBM. Median survival was 29.6 months. The dosing of VPA (Depakote) used in this trial was fairly high (12.5 mg/kg twice daily = 25 mg/kg daily).
    https://www.ncbi.nlm.nih.gov/pubmed/26194676

    The post-hoc analysis of prospective clinical trials by Happold et al. claiming that valproic acid confers no survival benefit, did not control for dose.
    https://www.ncbi.nlm.nih.gov/pubmed/26786929

    The 25 mg/kg daily used in the prospective trial above would equal 1500 mg Depakote daily for a 60 kg adult, while many brain tumor patients using Depakote as an anti-seizure med would have been using a lower dose, such as 500 mg twice daily.

    I provided a commentary on the debate around this study in the Valproic Acid section of the Treatment Options update at virtualtrials.com (Chapter 6)
    http://virtualtrials.com/pdf2017/treatment_options_gbm_2017.pdf


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  2. "Hence, we postulated that combination treatment with SAHA and CQ may lead to increased formation of autophagosomes, resulting in its hyper‑accumulation and ultimately inducing cell death in GBM cells. In the present study, we demonstrated that CQ co‑treatment enhanced SAHA‑mediated GBM cell apoptosis...
    ..The present study provides cellular and molecular evidence concerning the combined effect of SAHA and CQ which can be developed as a therapeutic strategy for the treatment of glioblastoma in the future."

    2018 https://www.ncbi.nlm.nih.gov/pubmed/29658588

    It's not a reason to think about adding Vorinostat to a cocktail for those who use Chloroquine?

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    Replies
    1. Vorinostat has poor brain permeability, with an unbound brain:plasma ratio of 0.01 in mice. Adding vorinostat to standard treatments in newly diagnosed GBM did not lead to improved survival.

      https://www.ncbi.nlm.nih.gov/pubmed/29016887

      Potent HDAC inhibitors with better brain permeability are needed.

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