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Repurposing Vorinostat for the Treatment of Disorders Affecting Brain

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Abstract

Based on the findings in recent years, we summarize the therapeutic potential of vorinostat (VOR), the first approved histone deacetylase (HDAC) inhibitor, in disorders of brain, and strategies to improve drug efficacy and reduce side effects. Scientific evidences provide a strong case for the therapeutic utility of VOR in various disorders affecting brain, including stroke, Alzheimer’s disease, frontotemporal dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, X‐linked adrenoleukodystrophy, epilepsy, Niemann-Pick type C disease, and neuropsychiatric disorders. Further elucidation of the neuroprotective and neurorestorative properties of VOR using proper clinical study designs could provide momentum towards its clinical application. To improve the therapeutic prospect, concerns on systemic toxicity and off-target actions need to be addressed along with the improvement in formulation and delivery aspects, especially with respect to solubility, permeability, and pharmacokinetic properties. Newer approaches in this regard include poly(ethylene glycol)-b-poly(dl-lactic acid) micelles, VOR-pluronic F127 micelles, encapsulation of iron complexes of VOR into PEGylated liposomes, human serum albumin bound VOR nanomedicine, magnetically guided layer-by-layer assembled nanocarriers, as well as convection-enhanced delivery. Even though targeting specific class or isoform of HDAC is projected as advantageous over pan-HDAC inhibitor like VOR, in terms of adverse effects and efficacy, till clinical validation, the idea is debated. As the VOR treatment-related adverse changes are mostly found reversible, further optimization of the therapeutic strategies with respect to dose, dosage regimen, and formulations of VOR could propel its clinical prospects.

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Abbreviations

ABCD1:

ATP‐binding cassette subfamily D member 1

BBB:

Blood–brain barrier

BDNF:

Brain-derived neurotrophic factor

cAMP:

Cyclic adenosine monophosphate

CREB:

CAMP response element binding protein

CRTC1:

CREB-regulated transcription coactivator 1

CBP:

CREB binding protein

CNS:

Central nervous system

CTCL:

Cutaneous T-cell lymphoma

DMSO:

Dimethyl sulfoxide

GBM:

Glioblastoma multiforme

GDNF:

Glial cell-derived neurotrophic factor

HATs:

Histone acetyltransferases

HDACs:

Histone deacetylases

Hsp:

Heat shock protein

iPSC:

Induced pluripotent stem cells

NPC:

Niemann-Pick Type C

NR2B:

N-Methyl-D-aspartate receptor 2 subunit B

PTCL:

Peripheral T-cell lymphoma

SAHA:

Suberoylanilide hydroxamic acid

SMA:

Spinal muscular atrophy

SMN:

Survival motor neuron

VLCFA:

Very long‐chain fatty acids

VOR:

Vorinostat

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Funding

The work was jointly supported by CSIR-Indian Institute of Chemical Technology, Hyderabad, and Amrita Vishwa Vidyapeetham, Kochi. IICT communication number generated by KIM division, CSIR-IICT [IICT/Pubs./2020/244], for this manuscript is duly acknowledged.

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  1. Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences Health Sciences Campus, Kochi, 682 041, Kerala, India

    Athira K. V.

  2. Department of Pharmaceutical Chemistry & Analysis, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Amrita Institute of Medical Sciences Health Sciences Campus, Kochi, 682 041, Kerala, India

    Prashant Sadanandan

  3. Applied Biology Division, CSIR- Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad, 500007, Telangana, India

    Sumana Chakravarty

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  1. Athira K. V.
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AKV and PS involved in conceptualization, data curation, formal analysis, funding acquisition, and writing–reviewing and editing. SC participated in formal analysis, funding acquisition, supervision, and writing—review and editing.

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Athira, K.V., Sadanandan, P. & Chakravarty, S. Repurposing Vorinostat for the Treatment of Disorders Affecting Brain. Neuromol Med 23, 449–465 (2021). https://doi.org/10.1007/s12017-021-08660-4

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