Beta-carotene inhibits tumor-specific angiogenesis by altering the cytokine profile and inhibits the nuclear translocation of transcription factors in B16F-10 melanoma cells.
Angiogenesis is the formation of new blood vessels out of the preexisting vascular network and involves a sequence of events that are of key importance in a broad array of physiological and pathological processes. The growth of tumor and metastasis are dependent on the formation of new blood vessels. The present study therefore aims at evaluating the antiangiogenic effect of beta-carotene using in vivo and in vitro models. Male C57BL/6 mice as well as B16F-10 cells were used for the experimental study. The in vivo study includes the inhibitory effect of beta-carotene on the formation of tumor-directed capillaries. Rat aortic ring assay, human umbilical vein endothelial cell proliferation, migration, and tube formation are used for assessing the in vitro antiangiogenic effect of beta-carotene. The differential regulation of proinflammatory cytokines as well as the inhibitory effect of beta-carotene on the activation and nuclear translocation of transcription factors are also assessed. Beta-carotene treatment significantly reduces the number of tumor-directed capillaries accompanied by altered serum cytokine levels. Beta-carotene is able to inhibit proliferation, migration, and tube formation of endothelial cells. Beta-carotene treatment downregulates the expression of matrix metalloproteinase (MMP)-2, MMP-9, prolyl hydroxylase, and lysyl oxidase gene expression and upregulates the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. The study reveals that beta-carotene treatment could alter proinflammatory cytokine production and could inhibit the activation and nuclear translocation of p65, p50, c-Rel subunits of nuclear factor-kappa B, and other transcription factors such as c-fos, activated transcription factor-2, and cyclic adenosine monophosphate response element-binding protein in B16F-10 melanoma cells. These observations show that beta -carotene exerts its antiangiogenic effect by altering the cytokine profile and could inhibit the activation and nuclear translocation of transcription factors.
Guruvayoorappan
C
C
Department of Immunology, Amala Cancer Research Centre, Amala Nagar, Kerala State, India.
Kuttan
Girija
G
D021581:Active Transport, Cell Nucleus; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D019207:beta Carotene / Q000008:administration & dosage / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D000975:Antioxidants; D016207:Cytokines; D016328:NF-kappa B; D019714:Tissue Inhibitor of Metalloproteinases; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D019207:beta Carotene; D020782:Matrix Metalloproteinases