Angiogenesis is a crucial step in the growth of cancer and its metastasis. It is regulated by several endogenous factors which may stimulate or inhibit the new blood vessel growth. Besides these endogenous factors, several exogenous factors including some natural compounds are known to modulate angiogenesis. Angiogenesis being a potential target for drugs against a number of pathological conditions, search for compounds from natural sources that can affect angiogenesis is of great interest. The objective of our present study was to understand the effect of chebulagic acid, a COX-LOX dual inhibitor isolated from the fruits of Terminalia chebula Retz., on angiogenesis. The model systems used were rat aortic rings and human umbilical vein endothelial cells. The results showed that chebulagic acid exerts an antiangiogenic effect. This was evidenced from decreased sprouting in rat aortic rings and decrease in biochemical markers in endothelial cells treated with chebulagic acid. It downregulated the production of CD31, E-selectin, and vascular endothelial growth factor in human umbilical vein endothelial cells in culture (HUVEC). Further studies to understand the molecular mechanism of action of chebulagic acid revealed that CA exerts its anti angiogenic effect by modulating VE cadherin- catenin signalling in human umbilical vein endothelial cells. 1. Introduction Angiogenesis, the regulated formation of new blood vessels from preexisting ones, plays a crucial role in organogenesis, advanced embryonic development, wound healing, and growth and action of female reproductive organs. Although angiogenesis is essential during these processes, in adulthood, it has a limited role in normal physiology and is mostly linked to pathological conditions such as tumorigenesis, rheumatoid arthritis, obesity, and diabetic retinopathy [1]. Angiogenesis is a complex and orderly process that involves cell-cell and cell-extracellular matrix interactions, which is controlled by a balance between angiogenic and angiostatic factors. Disruption of this balance leads to aberrant angiogenesis resulting in pathological conditions, arising due to hypo- or hyperangiogenesis [2]. The activation of endothelial cells, the initial step of angiogenesis, occurs when positive regulators predominate. The endothelial quiescence is achieved and maintained by the dominance of negative regulators [3, 4]. Apart from these endogenous factors, several exogenous factors are known to modulate angiogenesis. Naturally occurring bioactive compounds are gaining attention as therapeutic agents since they
References
[1]
D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011.
[2]
P. Carmeliet, “Blood vessels and nerves: common signals, pathways and diseases,” Nature Reviews Genetics, vol. 4, no. 9, pp. 710–720, 2003.
[3]
D. Hanahan and J. Folkman, “Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis,” Cell, vol. 86, no. 3, pp. 353–364, 1996.
[4]
N. Bouck, “Tumor angiogenesis: the role of oncogenes and tumor suppressor genes,” Cancer Cells, vol. 2, no. 6, pp. 179–185, 1990.
[5]
D. B. Reddy and P. Reddanna, “Chebulagic acid (CA) attenuates LPS-induced inflammation by suppressing NF-κB and MAPK activation in RAW 264.7 macrophages,” Biochemical and Biophysical Research Communications, vol. 381, no. 1, pp. 112–117, 2009.
[6]
D. B. Reddy, T. C. M. Reddy, G. Jyotsna et al., “Chebulagic acid, a COX-LOX dual inhibitor isolated from the fruits of Terminalia chebula Retz., induces apoptosis in COLO-205 cell line,” Journal of Ethnopharmacology, vol. 124, no. 3, pp. 506–512, 2009.
[7]
R. F. Nicosia and A. Ottinetti, “Growth of microvessels in serum-free matrix culture of rat aorta. A quantitative assay of angiogenesis in vitro,” Laboratory Investigation, vol. 63, no. 1, pp. 115–122, 1990.
[8]
E. A. Jaffe, R. L. Nachman, C. G. Becker, and C. R. Minick, “Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria,” The Journal of Clinical Investigation, vol. 52, no. 11, pp. 2745–2756, 1973.
[9]
M. S. Kiran, V. B. Sameer Kumar, R. I. Viji, and P. R. Sudhakaran, “Temporal relationship between MMP production and angiogenic process in HUVECs,” Cell Biology International, vol. 30, no. 9, pp. 704–713, 2006.
[10]
E. Engvall and P. Perlmann, “Enzyme-linked immunosorbent assay (ELISA) quantitative assay of immunoglobulin G,” Immunochemistry, vol. 8, no. 9, pp. 871–874, 1971.
[11]
H. Towbin, T. Staehelin, and J. Gordon, “Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications,” Proceedings of the National Academy of Sciences of the United States of America, vol. 76, no. 9, pp. 4350–4354, 1979.
[12]
B. Herren, B. Levkau, E. W. Raines, and R. Ross, “Cleavage of β-catenin and plakoglobin and shedding of VE-cadherin during endothelial apoptosis: evidence for a role for caspases and metalloproteinases,” Molecular Biology of the Cell, vol. 9, no. 6, pp. 1589–1601, 1998.
[13]
A. Tatsuguchi, K. Matsui, Y. Shinji et al., “Cyclooxygenase-2 expression correlates with angiogenesis and apoptosis in gastric cancer tissue,” Human Pathology, vol. 35, no. 4, pp. 488–495, 2004.
[14]
T. A. Martin, G. Watkins, J. Lane, and W. G. Jiang, “Assessing microvessels and angiogenesis in human breast cancer, using VE-cadherin,” Histopathology, vol. 46, no. 4, pp. 422–430, 2005.
[15]
M. G. Tonnesen, D. Jenkins Jr., S. L. Siegal, L. A. Lee, J. C. Huff, and R. A. Clark, “Expression of fibronectin, laminin, and factor VIII-related antigen during development of the human cutaneous microvasculature,” Journal of Investigative Dermatology, vol. 85, no. 6, pp. 564–568, 1985.
[16]
N. Ferrara, “VEGF and the quest for tumour angiogenesis factors,” Nature Reviews Cancer, vol. 2, no. 10, pp. 795–803, 2002.
[17]
R. I. Viji, V. B. Sameer Kumar, M. S. Kiran, and P. R. Sudhakaran, “Modulation of cyclooxygenase in endothelial cells by fibronectin: relevance to angiogenesis,” Journal of Cellular Biochemistry, vol. 105, no. 1, pp. 158–166, 2008.
[18]
S. J. Soumya, S. Binu, A. Helen, K. Anil Kumar, P. Reddanna, and P. R. Sudhakaran, “Effect of 15-lipoxygenase metabolites on angiogenesis: 15(S)-HPETE is angiostatic and 15(S)-HETE is angiogenic,” Inflammation Research, vol. 61, no. 7, pp. 707–718, 2012.
[19]
M. G. Lampugnani, M. Resnati, M. Raiteri et al., “A novel endothelial-specific membrane protein is a marker of cell-cell contacts,” Journal of Cell Biology, vol. 118, no. 6, pp. 1511–1522, 1992.
