Table 3 Preclinical studies with drugs targeting HIF-1, angiogenesis or vasculogenic mimicry in Uveal Melanoma

Chitosan

Induced cytotoxicity and reduced migration/invasion; reduced HIF-1α and VEGF expression

Xie L et al Int J Pharm 2020 [296]

AEZS-108

Upregulation of MASPIN/SERPINB5; downregulation HIF-1α and VEGF

Fodor K et al Oncotarget 2020 [299]

Arylsulfonamide 64B

Reduced hypoxia-induced expression of CXCR4 and c-Met, targeting HIF-1/p300/CBP binding

Dong L et al Clin Cancer Res 2019 [241]

Nutlin-3 in combination with RITA or Topotecan

Reduced in vitro and in vivo growth through downregulation of HIF-1α expression

De Lange J et al Oncogene 2012 [314]

Bevacizumab

Reduced in vitro angiogenesis and hepatic micrometastasis; decreased in vivo tumor growth, increased efficacy of radiotherapy in vitro and in vivo; decreased VEGFR2 and VEGF; increased growth of intraocularly injected tumors in mice

Yang H et al Investig Ophthalmol. Vis Sci 2010 [315];

Sudaka A et al Invest New Drugs. 2013 [316];

El Filali M et al Dev Ophthalmol 2012 [261]

Ranibizumab, humanized Fab-fragment against VEGF-A

Angiogenic potential of uveal melanoma cells, suppression of VEGF-A levels

Tura A et al Cancers 2019 [321]

Imatinib

Antagonization of temozolomide antiproliferative effect in vitro and improvement of the antitumor activity of temozolomide in vivo; reduced proliferation and invasion and upregulation of the tumor suppressor genes KISS1 and Maspin

Triozzi PL et al Melanoma Res 2008 [322]; Fernandes BF et al Anal Cell Pathol 2011 [324]

Lenalidomide and Sorafenib in combination

Synergistic inhibition of migration and formation of tubes in vitro, tumors growth and metastasis development in vivo

Mangiameli DP et al J Transl Med 2007 [325]

MLN4924 (Neddylation inhibition)

Reduced angiogenesis through NF-KB-mediated VEGFC secretion; NEDD8-activating enzyme inhibition; reduced expression of the Bcl-xL protein

Jin Y et al Clin Cancer Res 2018 [326];

Némati F et al PLoS One 2014 [327]

Genistein

Reduced vasculogenic mimicry through down-regulation of VE-cadherin; inhibition of ocular neovascularization blocking HIF-1α/VEGF axis

Cong R et al J Exp Clin Cancer Res 2009 [278]; Wang B et al Methods Find Exp Clin Pharmacol; Wang B et al J Ocul Pharmacol Ther 2005 [330]; Wang B et al J Ocul Pharmacol Ther 2003 [331]; Pan JS et al J Ocul Pharmacol Ther 2006 [332].

CMT-3, COL-3

Inhibition of vasculogenic mimicry through repression of MMP2, MMP9 and MT1-MMP

Seftor REB et al AACR 2002 [279]

Curcumin

Inhibition of vascular mimicry, endothelium-dependent vessels, EphA2, PI3K, MMP-2, and MMP-9 expression

Chen LX et al Cancer Biol Ther 2011 [335]