Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid

Area of Science:

• Pharmacology
• Oncology
• Molecular Biology

Background:

• Pathological angiogenesis is regulated by complex signaling pathways.
• Cyclooxygenase inhibitors and dithioles exhibit anti-angiogenic effects.

Purpose of the Study:

• To investigate the anti-angiogenic activities of novel anti-inflammatory drugs containing dithiolethione moieties (S-NSAIDs) and S-valproate.
• To compare the efficacy of S-NSAIDs and S-valproate against their parent compounds.

Main Methods:

• Assessed anti-angiogenic activities using human umbilical vein endothelial cells.
• Utilized muscle and tumor tissue explant angiogenesis assays.
• Evaluated developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos.

Main Results:

• S-NSAIDs and S-valproate inhibited endothelial cell proliferation and induced hsp27 phosphorylation.
• These novel compounds potently inhibited angiogenic responses in muscle and HT29 tumor explants.
• While dithiolethiones and valproic acid inhibited developmental angiogenesis, S-NSAIDs did not.

Conclusions:

• S-NSAIDs and S-valproate possess potent anti-angiogenic activities mediated by their dithiole moieties.
• The differential inhibition of pathological versus developmental angiogenesis suggests a role for these agents in cancer therapy.