Retinoic acid selectively inhibits the vascular permeabilizing effect of VPF/VEGF, an early step in the angiogenic cascade

Abstract

All-trans-retinoic acid (RA) and other retinoids modulate cell growth and differentiation, generally favoring terminal cell differentiation and inhibiting carcinogenesis.

Retinoids are also reported to inhibit angiogenesis and endothelial cell migration, actions that are also anti-carcinogenic.

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine secreted by many tumors. It renders microvessels hyperpermeable to plasma and stimulates endothelial cell migration and division.

To investigate further the mechanisms by which RA inhibits angiogenesis, we evaluated the effects of RA on VPF/VEGF-induced angiogenesis and microvascular permeability. RA selectively inhibited the angiogenic response induced by VPF/VEGF, but not that induced by fibroblast growth factor-2 (FGF-2), in the CAM assay.

RA and two of its isomers also inhibited the vascular permeabilizing effect of VPF/VEGF but not that induced by histamine. The vascular permeabilization induced by VPF/VEGF and blocked by RA takes place within 1-15 min, too short a time frame for RA to act by modulating transcription through classic retinoid receptors.

RA also inhibited VPF/VEGF-induced phosphorylation of PLC-gamma and synthesis of cGMP but actually increased VPF/VEGF binding to cultured endothelial cells.

Taken together, these findings indicate that RA selectively blocks VPF/VEGF-induced microvascular permeability and angiogenesis and also identify VPF/VEGF as a major target of RA action.

The selectivity of RA's action suggests that other, RA-independent pathways must exist for the angiogenesis induced by FGF-2 and the vascular permeabilizing effect of histamine.

 

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- Official Web Site: The Di Bella Method;

- The Di Bella Method (A Fixed Part - All-Trans Retinoic Acid, Analogues and/or Derivatives - Approximately 60mg per day orally: 40mg per day Beta-Carotene/β-Carotene, 10mg per day ATRA and 10mg per day Axerophthol palmitate);

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- Solution of retinoids in vitamin E in the Di Bella Method biological multitherapy;

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- Publication: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);

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- Recurrent Glioblastoma Multiforme (grade IV – WHO 2007): a case of complete objective response achieved by means of the concomitant administration of Somatostatin and Octreotide – Retinoids – Vitamin E – Vitamin D3 – Vitamin C – Melatonin – D2 R agonists (Di Bella Method – DBM) associated with Temozolomide;

- Chronic Lymphocytic Leukemia: Long-Lasting Remission with Combination of Cyclophosphamide, Somatostatin, Bromocriptine, Retinoids, Melatonin, and ACTH;

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- Oesophageal squamocellular carcinoma: a complete and objective response.