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Review
. 2009 Aug 8;280(2):145-53.
doi: 10.1016/j.canlet.2008.11.012. Epub 2008 Dec 25.

"VSports最新版本" Targeting tumor angiogenesis with histone deacetylase inhibitors

Leigh Ellis  1 , Hans Hammers, Roberto Pili
Affiliations
Review

Targeting tumor angiogenesis with histone deacetylase inhibitors (V体育2025版)

Leigh Ellis et al. Cancer Lett. .

Abstract (VSports手机版)

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-1alpha) signaling and its transcriptional target vascular endothelial growth factor (VEGF). Critical to HIF-1alpha signaling are post translational modifications including acetylation mediated by histone acetyltransferases (HATS) and deacetylation by histone deacetylases (HDACs) VSports手机版. More recently, HDACs were shown to be up-regulated in response to hypoxia mediating increased HIF-1alpha 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-1alpha and VEGF influence on tumor angiogenesis and how HDACs play a critical role in HIF-1alpha 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. .

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Figures (VSports在线直播)

Fig 1
Fig 1
Schematic cartoon demonstrating the regulation of HIF-1α transcriptional activity. Under normoxic conditions (top row) HIF-1α is hydroxylated, acetylated and bound by the von Hipple-Lindau (pVHL) ubiquitin E3 ligase complex, resulting in polyubiquitination and the proteosomal degradation of HIF-1α. Under hypoxic conditions (bottom row) HIF-1α hydroxylation and acetylation are inhibited due to low oxygen, stabilizing HIF-1α. HIF-1α translocates to the nucleus to bind HIF-1β and recruit CBP/p300 resulting in gene transcription. Hypoxia also induces HDAC expression (middle row) which deacetylates HIF-1α either directly or indirectly to increase HIF-1α transcriptional activity. HDAC inhibition reverses the activity of HDACs resulting in the degradation of HIF-1α.
Fig 2
Fig 2
Schematic cartoon representing the strategies to treat solid tumor patients with metastatic disease. HDACI will be combined with TKI, monoclonal antibody or mTOR inhibitors.
See this image and copyright information in PMC

References

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