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Prodrug of green tea epigallocatechin-3-gallate (Pro-EGCG) as a potent anti-angiogenesis agent for endometriosis in mice

Abstract

Green tea epigallocatechin-3-gallate (EGCG) can inhibit angiogenesis and development of an experimental endometriosis model in mice, but it suffers from poor bioavailability. A prodrug of EGCG (pro-EGCG, EGCG octaacetate) is utilized to enhance the stability and bioavailability of EGCG in vivo. In this study, the potential of pro-EGCG as a potent anti-angiogenesis agent for endometriosis in mice was investigated. Homologous endometrium was subcutaneously transplanted into mice to receive either saline, vitamin E, EGCG or pro-EGCG treatment for 4 weeks. The growth of the endometrial implants were monitored by IVIS® non-invasive in vivo imaging during the interventions. Angiogenesis of the endometriotic lesions was determined by Cellvizio® in vivo imaging and SCANCO® Microfil microtomography. The bioavailability, anti-oxidation and anti-angiogenesis capacities of the treatments were measured in plasma and lesions. The implants with adjacent outer subcutaneous and inner abdominal muscle layers were collected for histological, microvessel and apoptosis examinations. The result showed that EGCG and pro-EGCG significantly decreased the growth of endometrial implants from the 2nd week to the 4th week of intervention. EGCG and pro-EGCG significantly reduced the lesion size and weight, inhibited functional and structural microvessels in the lesions, and enhanced lesion apoptosis at the end of interventions. The inhibition by pro-EGCG in all the angiogenesis parameters was significantly greater than that by EGCG, and pro-EGCG also had better bioavailability and greater anti-oxidation and anti-angiogenesis capacities than EGCG. Ovarian follicles and uterine endometrial glands were not affected by either EGCG or pro-EGCG. Vitamin E had no effect on endometriosis. In conclusion, pro-EGCG significantly inhibited the development, growth and angiogenesis of experimental endometriosis in mice with high efficacy, bioavailability, anti-oxidation and anti-angiogenesis capacities. Pro-EGCG could be a potent anti-angiogenesis agent for endometriosis.

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Acknowledgments

We thank Dr. Sreedhar Pamu of McGill University for technical assistance in providing the pro-EGCG. The work was supported partially by an Academic Equipment Grant 2009/10 (3029821) from the Chinese University of Hong Kong to C.C.W. for the In vivo Cellular Imaging System; a Global Scholarship Programme for Research Excellence—CNOOC Grant 2008–2009 from The Chinese University of Hong Kong to H.X. and C.C.W. for training in the non-invasive live animal in vivo imaging in Harvard University.

Conflict of interest

T.H.C. declares that he is the inventor of the issued patent claiming the use of pro-EGCG for proteasome inhibition and the treatment of cancer. The other authors declare there is no conflict of interest.

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Correspondence to Chi Chiu Wang.

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Wang, C.C., Xu, H., Man, G.C.W. et al. Prodrug of green tea epigallocatechin-3-gallate (Pro-EGCG) as a potent anti-angiogenesis agent for endometriosis in mice. Angiogenesis 16, 59–69 (2013). https://doi.org/10.1007/s10456-012-9299-4

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  • DOI: https://doi.org/10.1007/s10456-012-9299-4

Keywords

  • Endometriosis
  • Anti-angiogenesis
  • Green tea
  • Epigallocatechin-3-gallate