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Histones and lung cancer: are the histone deacetylases a promising therapeutic target?

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Abstract

Purpose

Deoxyribonucleic acid is wrapped around an octamer of core histone proteins to form a nucleosome, the basic structure of chromatin. Two main families of enzymes maintain the equilibrium of acetyl groups added to or removed from lysine residues. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysine residues in histone amino termini and non-histone proteins also, leading to chromatin condensation and transcriptional repression. HDAC overexpression, resulting in tumor suppressor genes silencing, has been found in several human cancer tissues, indicating that aberrant epigenetic activity is associated with cancer development. Therefore, inhibitors of these enzymes are emerging anticancer agents and there is evidence supporting their role in hematological malignancies. The minimal efficacy of conventional chemotherapy has prompted a renewed focus on targeted therapy based on pathways altered during the pathogenesis of lung cancer. We identify the pleiotropic antitumor effects of HDAC inhibitors in lung cancer, focusing on the result caused by their use individually, as well as in combination with other chemotherapeutic agents, in lung cancer cell lines and in clinical trials.

Method

We searched reviews and original papers in Pubmed over the last 10 years.

Results

We identified 76 original papers on this topic.

Conclusions

Numerous preclinical studies have shown that HDAC inhibitors exhibit impressive antitumor activity in lung cancer cell lines. Nevertheless, Phase III randomized studies do not support HDAC inhibitors use in lung cancer patients in everyday practice. Ongoing and future studies would help determine their role in lung cancer treatment.

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Abbreviations

HAT:

Histone acetyltransferase

HDAC:

Histone deacetylase

HDACIs:

Histone deacetylase inhibitors

TKIs:

Tyrosine kinase inhibitors

NF-kB:

Nuclear factor kB

COX:

Cyclooxygenase

HIF-1α:

Hypoxia-inducible factor-1-alpha

VEGF:

Vascular endothelial growth factor

EGFR:

Endothelial growth factor receptor

TRAIL:

Tumor necrosis factor-related apoptosis inducing ligand

IGFBP:

Insulin-like growth factor binding protein

VPA:

Valproic acid

NaB:

Sodium butyrate

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  1. Oncology Unit, Third Department of Internal Medicine, Sotiria General Hospital, Athens University School of Medicine, 152 Mesogeion Av., 11527, Athens, Greece

    Vasiliki Petta, Ioannis Gkiozos, Alex Strimpakos & Konstantinos Syrigos

  2. Yale School of Medicine, New Haven, CT, USA

    Konstantinos Syrigos

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Petta, V., Gkiozos, I., Strimpakos, A. et al. Histones and lung cancer: are the histone deacetylases a promising therapeutic target?. Cancer Chemother Pharmacol 72, 935–952 (2013). https://doi.org/10.1007/s00280-013-2223-9

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