Antiangiogenic properties of selected ruthenium(III) complexes that are nitric oxide scavengers

L Morbidelli1, S Donnini, S Filippi

  • 1Department of Molecular Biology, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.

Insights

Ruthenium compounds NAMI-A, KP1339, and RuEDTA effectively scavenge nitric oxide (NO), inhibiting angiogenesis and showing potential as anti-cancer agents by blocking tumor growth and spread.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Cancer Research

Background:

  • The nitric oxide synthase (NOS) pathway regulates angiogenesis, with elevated nitric oxide (NO) linked to tumor progression.
  • Targeting the NOS pathway offers potential therapeutic strategies for angiogenesis-dependent tumors.

Purpose of the Study:

  • To pharmacologically characterize ruthenium-based compounds (NAMI-A, KP1339, RuEDTA) as potential nitric oxide (NO) scavengers for antiangiogenic and antitumour applications.

Main Methods:

  • In vitro assessment of NO scavenging by ruthenium compounds using spectroscopy (electronic absorption, FT-IR, 1H-NMR).
  • Evaluation of effects on endothelium-dependent vasorelaxation in rabbit aorta rings.
  • Inhibition assays for vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation and migration.
  • In vivo studies using NAMI-A to assess angiogenesis inhibition.

Main Results:

  • NAMI-A, KP1339, and RuEDTA demonstrated potent NO scavenging capabilities, forming stable ruthenium-NO adducts.
  • These compounds inhibited endothelium-dependent vasorelaxation, an effect reversible by 8-Br-cGMP.
  • Ruthenium compounds effectively blocked VEGF- or NO-stimulated endothelial cell proliferation and migration without exhibiting cytotoxicity.
  • NAMI-A significantly inhibited VEGF-induced angiogenesis in vivo.

Conclusions:

  • Ruthenium-based compounds NAMI-A, KP1339, and RuEDTA function as effective NO scavengers.
  • Their NO-scavenging activity underlies their antiangiogenic and potential antitumour properties, particularly in angiogenesis-dependent cancers.

Related Concept Videos

Mechanism of Angiogenesis01:10

Mechanism of Angiogenesis

Blood vessel formation starts early during embryonic development, around day 7. In the extraembryonic yolk sac, mesodermal precursor cells called hemangioblast proliferate and differentiate into angioblast. Angioblasts express vascular endothelial growth factor receptor 2 or VEGFR2, which binds VEGF-A, a proangiogenic factor, guiding blood vessel formation. VEGF signaling promotes angioblasts to form a blood island in the developing embryo. Angioblasts further differentiate, giving rise to...
Nitric Oxide Signaling Pathway01:28

Nitric Oxide Signaling Pathway

Nitric oxide (NO), an inorganic gas, acts as a potent second messenger in most animal and plant tissues. NO diffuses out of the cells that produce it and enters the neighboring cells to generate a downstream response. NO synthase (NOS) catalyzes NO production by the deamination of the amino acid arginine. There are three isoforms of NOS. Endothelial cells have endothelial NOS (eNOS), nerve and muscle cells have neuronal NOS (nNOS), and macrophages produce inducible NOS (iNOS) upon exposure to...
Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists01:23

Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists

Prostacyclin receptor agonists are a class of therapeutic agents integral to managing pulmonary arterial hypertension (PAH). These drugs operate by mimicking the action of prostaglandin I2, or PGI2, a naturally occurring compound in the body.
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...