Allyl isothiocyanate (AITC) and phenyl isothiocyanate (PITC) inhibit tumour-specific angiogenesis by downregulating nitric oxide (NO) and tumour necrosis factor-α (TNF-α) production

• Published in: Nitric oxide 2007-03, Vol.16 (2), p.247-257
• Main Authors: Thejass, Punathil, Kuttan, Girija
• Format: Article
• Language: English
• Subjects: Allyl isothiocyanate; Angiogenesis; Animals; Aorta - drug effects; Cell Line, Tumor; Down-Regulation - drug effects; In Vitro Techniques; Isothiocyanates - pharmacology; Macrophage; Macrophages - drug effects; Macrophages - metabolism; Male; Melanoma, Experimental - blood supply; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neovascularization, Pathologic; Nitric oxide; Nitric Oxide - biosynthesis; Phenyl isothiocyanate; Rats; Tumor Necrosis Factor-alpha - biosynthesis; Tumour necrosis factor-α
• ISSN: 1089-8603; 1089-8611
• DOI: 10.1016/j.niox.2006.09.006

Angiogenesis, a crucial step in the growth and metastasis of cancers, is initiated with vasodilation mediated by nitric oxide (NO). The pro-inflammatory cytokine, tumour necrosis factor-α (TNF-α), is a mediator of nitric oxide synthesis. We analyzed the effect of allyl isothiocyanate (AITC) and phenyl isothiocyanate (PITC) on serum NO as well as TNF-α level during angiogenesis. In vivo antiangiogenic activity was studied using B16F-10 melanoma cell-induced capillary formation in C57BL/6 mice. Intraperitoneal administration of AITC and PITC at a concentration of 25 μg/dose/animal significantly inhibited tumour-directed capillary formation. Treatment of AITC and PITC significantly downregulated serum NO as well as TNF-α level in angiogenesis-induced animals compared to untreated control animals. The in vitro antiangiogenic study, using rat aortic ring assay, showed that both AITC and PITC at non-toxic concentrations inhibited the production of proangiogenic factors from B16F-10 melanoma cells which was evident with the inhibition of microvessel outgrowth from aortic rings. Both AITC and PITC significantly inhibited sodium nitroprusside as well as TNF-α-induced microvessel outgrowth from rat aortic ring. Administration of AITC and PITC also significantly reduced NO and TNF-α production by LPS-stimulated macrophages both in vivo as well as in vitro. Bio-assay using serum of angiogenesis-induced animals and supernatant from LPS-stimulated macrophages clearly confirmed the downregulatory action of AITC and PITC on TNF-α production. These results clearly demonstrated that AITC and PITC inhibited tumour-specific angiogenesis by downregulating NO and TNF-α production.