13 cis-retinoic acid regulates cytokine production and inhibits angiogenesis by disrupting endothelial cell migration and tube formation.

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.