Cancer Letters

Cancer Letters

Volume 280, Issue 2, 8 August 2009, Pages 145-153
Cancer Letters

Mini-review
Targeting tumor angiogenesis with histone deacetylase inhibitors

https://doi.org/10.1016/j.canlet.2008.11.012Get rights and content

Abstract

Solid tumor malignancies including breast, lung and prostate carcinomas are considered to be angiogenesis dependent. Tumor angiogenesis is often mediated by hypoxia secondary to tumor growth or by increased oncogenic signaling. Both mechanisms result in increased hypoxia-inducible factor-1 alpha (HIF-1α) signaling and its transcriptional target vascular endothelial growth factor (VEGF). Critical to HIF-1α signaling are post translational modifications including acetylation mediated by histone acetyltransferases (HATS) and deacetylation by histone deacetylases (HDACs). More recently, HDACs were shown to be up-regulated in response to hypoxia mediating increased HIF-1α signaling. HDAC inhibitors represent a new class of anti-cancer therapeutics which show great promise at inhibiting angiogenesis in pre-clinical animal models and early phase clinical trials. This review will discuss the role of HIF-1α and VEGF influence on tumor angiogenesis and how HDACs play a critical role in HIF-1α transcriptional activity. Furthermore it will also be discussed how targeting HDACs via their inhibition create new avenues in treating solid malignancies by increasing the activity of established and novel therapeutic applications.

Introduction

Angiogenesis describes the formation of new blood vessels from the existing vasculature and is required for the promotion of fundamental physiological processes including embryonic development, fertility and tissue repair [1]. While angiogenesis has strong implications in homeostasis, it also has the potential to promote tumor growth and metastasis [1], [2]. Within tumors, new blood vessel formation can occur by sprouting from pre-existing vasculature which maybe assisted by the recruitment of circulating cells such as bone marrow derived endothelial progenitor cells, macrophages and fibroblasts [3], [4]. These cells along with malignant cells are able to secrete pro-angiogenic factors including vascular endothelial growth factor (VEGF), which induce tumor blood vessel formation [5].

The transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) regulates the expression of numerous genes involved in various cellular signaling pathways including angiogenesis via the increased expression of VEGF [6]. Over-expression of VEGF mediated by the stabilization of HIF-1α has been identified in multiple malignancies [6] and for this reason targeting the tumor vasculature via the inhibition of VEGF either directly or indirectly has become an attractive target in novel anti-cancer drug development.

This review will focus on the regulation of HIF-1α transcriptional activity by histone deacetylases (HDACs), the anti-angiogenic properties of HDAC inhibitors and their implications as anti-angiogenic agents in treating patients either as a monotherapy or in combination with other available chemotherapy agents.

Section snippets

HIF-1 and angiogenesis

The HIF protein family of transcription factors consists of a constitutively expressed beta subunit HIF-1β whose mRNA and protein levels remain constant and are not regulated by oxygen levels [7] and three alpha subunits; HIF-1α, HIF-2α and HIF-3α which are tightly regulated by oxygen tension levels within a cell [8]. While HIF-2α and HIF-3α are expressed in selected tissues [9], HIF-1α is ubiquitously expressed in both human and mouse tissue and studies have revealed HIF-1α to be the primary

HIF-1 and cancer

Angiogenic growth factors, in particular VEGF, and enzymes involved in glucose metabolism exhibit increased expression in malignant tissue when compared to normal tissue. This is due largely to the overexpression of HIF-1α which is observed in various tumors including breast, prostate, brain, lung and head and neck [19], [20]. HIF-1α expression often increases in response to tumor cell proliferation and intratumoral hypoxia, as well as genetic alterations resulting in the activation of

HDAC, HDAC inhibition and angiogenesis

The primary role of HDACs is to oppose the activity of histone acetyltransferases (HATs). HDACs remove the acetyl groups from lysine residues of both histone and non-histone proteins [41]. HDACs can be divided into four classes: class I consists of HDAC 1, 2, 3 and 8 (nuclear localization), class II consists of HDAC 4, 5, 6, 7, 9 and 10 (cytoplasm and nuclear localization), class III consists of sirtuins (SIRT1-7) and class IV consists of HDAC 11 which exhibits features of both classes I and II

HDAC inhibitors in combination to target angiogenesis

More over HDACI as monotherapy are displaying promising, although limited responses in the clinic and therefore their role in combination therapy may see HDACI reach their full potential as anti-cancer agents.

While HDACI are being combined with multiple anti-cancer agents (both novel and conventional) [41], only a few strategies targeting angiogenesis are currently under development that may show promise to clinical translation. As mentioned previously, the development and use of tyrosine

Clinical application of HDACI targeting angiogenesis

While numerous clinical trial data has been published involving patients with various cancers being treated with HDACI, only few reports include correlative studies which investigate the mechanisms behind HDACI success in the clinic. Of the published data two recent reports on patients with refractory cutaneous T cell lymphoma (CTCL) indicate that the anti-angiogenic actions of HDACI may potentiate the clinical response noted in patients. In a phase II trial reported by Duvic et al. refractory

Conclusion

As a better understanding of the pivotal role of angiogenesis in tumor biology is put together, it has been revealed that HIF-1α and its transcriptional product VEGF are key mediators of the response to tumor-induced hypoxia. For this reason targeting VEGF either directly or indirectly has become an attractive target of therapeutic approaches. Inhibiting VEGF specifically or the VEGF signaling pathway returned promising results though escape mechanisms counter acted the actions of the drugs,

Disclosure

Dr. Roberto Pili receives grant funding from Schering AG and Pfizer pharmaceuticals.

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