Hypoxia-selective inhibition of angiogenesis development by NAMI-A analogues.
The antimetastatic ruthenium(III) complex (H2Im)[trans-RuCl4(HIm)(DMSO)] (NAMI-A) as well as its two analogues (H2Ind)[trans-RuCl4(HInd)(DMSO)] (Ru-Ind) and (HIsq)[trans-RuCl4(Isq)(DMSO)] (Ru-Isq) (HIm-imidazole, HInd-indazole, Isq-isoquinoline, DMSO-dimethyl sulfoxide) were tested for their effect on endothelial cell functions in vitro on human skin microvascular endothelial cells (HSkMEC) and human endothelial progenitor cells (HPEC-CB.2) under normoxic (21 % O2) and hypoxic (1 % O2) conditions. All studied complexes showed very low cytotoxicity profiles towards both mature microvascular and precursor endothelial cells (ECs), independently of oxygen concentration. Among tested compounds Ru-Ind exhibited the highest cytotoxicity. The antiangiogenic activity of ruthenium complexes was evaluated for their influence on pseudo-vessels formation by microvascular endothelial cells (HSkMEC) because of their involvement in melanoma progression. Our studies indicated that Ru-Ind and Ru-Isq exhibited hypoxia- and dose-dependent-inhibition of angiogenesis on Matrigel™. Significant hypoxia-selective downregulation of pseudo-vessels formation by Ru-Isq correlates with efficient inhibition of cell motility. Interestingly, in the applied concentration doses migration of endothelial cells was also inhibited by NAMI-A, but the pseudo-vessels formation on Matrigel™ was unaffected. Angiogenesis-related genes expression profile for both mature and precursor ECs indicated that inhibition of angiogenesis, mainly due to Ru-Isq, as compared to NAMI-A and Ru-Ind correlated with downregulation of CD31 and CD144 expression and upregulation of NOTCH4 expression in mature ECs, which is essential for endothelial cell motility and stalk cells organization control. The hypoxia-selective antiangiogenic activity of Ru-Ind and Ru-Isq, NAMI-A analogues makes them potent antimetastatic therapeutics for their selective action in hypoxia which controls tumor pathologic angiogenesis.
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060, Kraków, Poland. maria.oszajca@chemia.uj.edu.pl.
Maria
M
Oszajca
Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, 45071, Orléans, France.
Guillaume
G
Collet
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060, Kraków, Poland.
Grażyna
G
Stochel
Centre for Molecular Biophysics, Cell Recognition and Glycobiology, UPR4301-CNRS, rue Charles Sadron, 45071, Orléans, France. claudine.kieda@cnrs-orleans.fr.|Malopolska Biotechnology Centre, Jagiellonian University, Kraków, Poland. claudine.kieda@cnrs-orleans.fr.
Claudine
C
Kieda
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060, Kraków, Poland.
Małgorzata
M
Brindell
D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009389:Neovascularization, Pathologic / Q000235:genetics; D009942:Organometallic Compounds / Q000737:chemistry*; D012428:Ruthenium / Q000737:chemistry*; D017975:Ruthenium Compounds; D000072258:Tumor Hypoxia / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D012428:Ruthenium; D004121:Dimethyl Sulfoxide
Angiogenesis; Endothelial cells; Hypoxia; NAMI-A analogues; Ruthenium complexes