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.

Targeting oxidative stress to treat endometriosis

“…Paul S et al [112] Animal study MMP-3 activity reduction, significant regression of glandular epithelium, increased apoptotic cells Diminished activator protein (AP)-1 DNA-binding activity, reduced Bcl-2 expression along with increased Bax expression andcaspase-9 activation Xanthohumol Rudzitis-Auth J et al [120] Animal study Reduction of implant size, lesions vascularization Reduced level of phosphoinositide 3-kinase protein EGCG drug and pro-drug Wang et al [127] Animal study Decrease in growth of endometrial implants, lesions size and weight, inhibition of functional and structural microvessels, enhanced lesion apoptosis Anti-angiogenesis through inhibitory effects on VEGF expression and receptor activity, anti-oxidation capacities…”

“…Vitamin E had no effect on the inspected endometriosis parameters. In their conclusion, the authors stated that pro-EGCG has a high efficacy, bioavailability, antioxidation and anti-angiogenesis capacities and could be a potent antiangiogenesis agent for endometriosis [127].…”

“…A synthetic derivative of EGCG, obtained by acetylation of EGCG, was suggested to be used as a pro-drug of EGCG with improved stability and better bioavailability [127]. The researchers compared the effect of saline, Vitamin E, EGCG or pro-EGCG on mice with subcutaneously transplanted endometrium.…”

Development of a subcutaneous endometriosis rat model

“…In this study, one micro-organism was used and this could modify the pathophysiology of endometriosis 18 . Wang et al 19 used nude mice implanted autologous endometrium in the subcutaneous pouch, but did not describe how the bag. In this work, it was also used animal with modified immune system may therefore alter the pathophysiology of endometriosis 19 .…”

“…Wang et al 19 used nude mice implanted autologous endometrium in the subcutaneous pouch, but did not describe how the bag. In this work, it was also used animal with modified immune system may therefore alter the pathophysiology of endometriosis 19 . Fu et al 20 implanted autologous fragments of uterus in a subcutaneous pocket, but ommited details of the bag's construction 20 .…”