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.