title: 13 cis-retinoic acid regulates cytokine production and inhibits angiogenesis by disrupting endothelial cell migration and tube formation.
abstract: Cancer prevention using natural products has become an integral part of cancer control. In this study we investigated the effect of 13-cis-retinoic acid on the inhibition of angiogenesis using in vivo as well as in vitro models. Our studies using animal model reveled that 13-cis-retinoic acid could significantly (p < 0.001) inhibit the tumor directed capillaries. The cytokine profile in the serum of these animals showed a drastically increased level of proinflammatory cytokines such as IL-1beta, TNF-alpha, IL-6, GM-CSF and the direct endothelial cell proliferating agent, VEGF during the onset of angiogenesis. Administration of 13-cis-retinoic acid could differentially regulate these cytokine's elevation. The differential elevation is further evidenced by the increased production of IL-2 and tissue inhibitor of metalloprotease-1 (TIMP-1) in the 13-cis-retinoic acid treated animals. Aortic ring assay for in vitro angiogenesis revealed that 13-cis-retinoic acid could markedly inhibit the microvessel sprouting. Moreover, 13-cis-retinoic acid was able to inhibit vascular endothelial cell proliferation, migration and tube formation. Furthermore, 13-cis-retinoic acid treatment could inhibit the activation and nuclear translocation of p65, p50, c-Rel subunits of nuclear factor-KB, 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 findings suggest that the anti-angiogenic potential of 13-cis-retinoic acid is mediated through inhibition of endothelial cell migration and tube formation and altered cytokine production during the onset of angiogenesis.
authors.affiliation: Department of Immunology, Amala Cancer Research Centre, Amala Nagar, Thrissur 680 555, Kerala State, India.
authors.forename: Chandrasekharan
authors.initials: C
authors.lastname: Guruvayoorappan
authors.forename: Girija
authors.initials: G
authors.lastname: Kuttan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015474:Isotretinoin / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D016207:Cytokines; D016328:NF-kappa B; D014157:Transcription Factors; D015474:Isotretinoin