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  • Title: 13 cis-retinoic acid regulates cytokine production and inhibits angiogenesis by disrupting endothelial cell migration and tube formation.
    Author: Guruvayoorappan C, Kuttan G.
    Journal: J Exp Ther Oncol; 2008; 7(3):173-82. PubMed ID: 19066126.
    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.
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