Sponge-derived acetylenic alcohols, petrosiols, inhibit proliferation and migration of platelet-derived growth factor (PDGF)-induced vascular smooth muscle cells

Bioorg Med Chem. 2013 Apr 1;21(7):1804-10. doi: 10.1016/j.bmc.2013.01.039. Epub 2013 Jan 31.

Abstract

Platelet-derived growth factor (PDGF) induces the proliferation and migration of vascular smooth muscle cells (VSMCs), leading to the development of various vascular disorders such as restenosis and atherosclerosis. Therefore, inhibitors of PDGF-induced cellular events would be candidate agents for treating these diseases. During the search for such inhibitors from marine sources, we isolated petrosiols A-D (1-4) and related compounds from the marine sponge Petrosia strongylata. These metabolites, which we previously reported as neurotrophic substances, showed an inhibitory effect on PDGF-induced DNA synthesis at IC50 values of 0.69-2.2 μM. Petrosiol A (1) inhibited PDGF-induced cell proliferation without remarkable cytotoxicity and arrested cell cycle progression from the G0/G1 to S phase by inducing the downregulation of the expression of G1 checkpoint proteins cyclin D1, cyclin E, cyclin-dependent kinases (CDK)2, and CDK4 and the upregulation of the expression of p21 and p27. In addition, petrosiol A (1) inhibited the phosphorylation of PDGF receptor-β and its downstream proteins such as phospholipase C (PLC)-γ1, Akt, and extracellular signal-regulated kinase (ERK)1/2. These results suggest that 1 inhibited PDGF-induced VSMC proliferation by interrupting the phosphorylation of PDGF receptor-β followed by downstream signal transduction. Furthermore, petrosiol A (1) suppressed PDGF-induced actin filament dissociation and cell migration, suggesting that 1 and its derivatives may be used for the prevention and treatment of vascular diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Alcohols / chemistry*
  • Alcohols / isolation & purification
  • Alcohols / pharmacology*
  • Alkynes / chemistry*
  • Alkynes / isolation & purification
  • Alkynes / pharmacology*
  • Animals
  • Aorta / cytology
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects*
  • DNA / metabolism
  • Humans
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / metabolism
  • Platelet-Derived Growth Factor / metabolism*
  • Porifera / chemistry*
  • Signal Transduction / drug effects

Substances

  • Actins
  • Alcohols
  • Alkynes
  • Cell Cycle Proteins
  • Platelet-Derived Growth Factor
  • DNA