Allyl isothiocyanate (AITC) and phenyl isothiocyanate (PITC) inhibit tumour-specific angiogenesis by downregulating nitric oxide (NO) and tumour necrosis factor-alpha (TNF-alpha) production.
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-alpha (TNF-alpha), 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-alpha 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 microg/dose/animal significantly inhibited tumour-directed capillary formation. Treatment of AITC and PITC significantly downregulated serum NO as well as TNF-alpha 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-alpha-induced microvessel outgrowth from rat aortic ring. Administration of AITC and PITC also significantly reduced NO and TNF-alpha 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-alpha production. These results clearly demonstrated that AITC and PITC inhibited tumour-specific angiogenesis by downregulating NO and TNF-alpha production.
Thejass
Punathil
P
Department of Immunology, Amala Cancer Research Centre, Amala Nagar, Thrissur, Kerala 680 555, India.
Kuttan
Girija
G
D000818:Animals; D001011:Aorta / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D066298:In Vitro Techniques; D017879:Isothiocyanates / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000096:biosynthesis*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D017879:Isothiocyanates; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide