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Epigenetic approach for angiostatic therapy: promising combinations for cancer treatment

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Abstract

Cancer cells are often dependent on epigenetic pathways for their survival. Consequently, drugs that target the epigenome, rather than the underlying DNA sequence, are currently attracting considerable attention. In recent years, the first epigenetic drugs have been approved for cancer chemotherapy, mainly for hematological applications. Limitations in single-drug efficacies have thus far limited their application in the treatment of solid tumors. Nevertheless, promising activity for these compounds has been suggested when combined with other, distinctly targeted agents. In this review, we discuss the anti-angiogenic activity of histone deacetylase and DNA methyltransferase inhibitors and their combinations with other targeted (anti-angiogenic) therapeutics in treatment of solid tumors. The role that these inhibitors play in the inhibition of tumor angiogenesis, particularly in combination with other targeted agents, and the advantages they present over broad acting anticancer agents, are critically discussed.

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Abbreviations

5FD:

5-Fluoro-2′-deoxycytidine

Ang-2:

Angiopoietin2

AML:

Acute myeloid leukemia

AZA:

Azacitidine, 5-AZA-CR, 5-azacytidine

bFGF:

Basic fibroblast growth factor

FGFR:

Fibroblast growth factor receptor

CAM:

Chorioallantoic membrane of the chicken embryo

CTCL:

Cutaneous T cell lymphoma

CYR61:

Cysteine-rich angiogenic inducer 61

DAC:

Decitabine, 5-AZA-2′-deoxycytidine, 5-AZA-CdR

DNMT:

DNA methyltransferase

E-cadherin:

Epithelial cadherin

EC:

Endothelial cells

EGCG:

Epigallocatechin gallate

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

eNOS:

Endothelial nitric oxide synthase (eNOS)

FAO:

Fatty acid oxidation

FSC:

Feedback system control

HAT:

Acetyltransferase

HDAC:

Histone deacetylase

HIF-1α:

Hypoxia-inducible factor 1 alpha

HUVEC:

Human umbilical vein endothelial cells

HYD:

Hydralazine

IC50 :

The half maximal inhibitory concentration

IGF1:

Insulin-like growth factor 1

IL:

Interleukin

KP1019:

trans-[Tetrachlorobis(1H-indazole)ruthenate(III)

miRNA:

Noncoding microRNA

MMP:

Matrix metalloproteinase

MTA1:

Metastasis-associated protein 1

mTOR:

Mechanistic target of rapamycin

MVD:

Microvessel density

NAMI-A:

trans-[Tetrachloro(dimethylsulfoxide)(imidazole)ruthenate(III)]

NOX4:

NADPH oxidase 4

NSCLC:

Non-small cell lung cancer

NuRD:

Nucleosome remodeling and deacetylase

OS:

Overall survival

p300-HAT:

p300 histone acetyltransferase

PBA:

Phenylbutyrate

PDGF-B:

Platelet-derived growth factor subunit B

PDGFR-B:

Platelet-derived growth factor subunit B receptor

PFS:

Progression-free survival

PVRL2:

Poliovirus receptor-related 2

RAPTA-C:

Ru(η6-p-cymene)(pta)Cl2

RAPTA-T:

Ru(η6-toluene)(pta)Cl2

RCC:

Renal cell carcinoma

SAHA:

Vorinostat

SAM:

S-adenosyl methionine

siRNA:

Small interfering RNA

SIRT:

Histone deacetylase sirtuins

TGF-β:

Transforming growth factor beta

TIMP3:

Tissue inhibitor of matrix metalloproteinase 3

Tie-2:

Angiopoietin 1 receptor

TKI:

Tyrosine kinase inhibitor

TSA:

Trichostatin A

TSG:

Tumor suppressor gene

TSP-1:

Thrombospondin 1

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

VE-cadherin:

Vascular endothelial cadherin

VHL:

Von Hippel–Lindau

VPA:

Valproic acid

WIF-1:

Wnt inhibitory factor 1

ZEB:

Zebularine

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Acknowledgements

We thank the European Research Council (ERC-StG-2015-680209 to PNS) and the Dutch Cancer Society (VU2014-7234 to AWG and PNS) for financial support.

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  1. Robert H. Berndsen and U. Kulsoom Abdul have contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, VU University Medical Center, 1007, MB, Amsterdam, The Netherlands

    Robert H. Berndsen, U. Kulsoom Abdul, Marije T. te Winkel & Arjan W. Griffioen

  2. School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland

    Andrea Weiss, Marloes Zoetemelk & Patrycja Nowak-Sliwinska

  3. Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology, 1015, Lausanne, Switzerland

    Paul J. Dyson

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  1. Robert H. Berndsen
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Correspondence to Patrycja Nowak-Sliwinska.

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Berndsen, R.H., Abdul, U.K., Weiss, A. et al. Epigenetic approach for angiostatic therapy: promising combinations for cancer treatment. Angiogenesis 20, 245–267 (2017). https://doi.org/10.1007/s10456-017-9551-z

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