Anti-angiogenic potential of an ethanol extract of Annona atemoya seeds in vitro and in vivo

Abstract

BackgroundAngiogenesis, which is initiated by certain tumor micro-environmental conditions and diverse protein factors, plays a pivotal role during tumor development and metastasis. Therefore, many efforts have been made to develop effective anti-angiogenic agents as anticancer therapeutics. In the current study, we investigated the anti-angiogenic potential of an ethanol extract of Annona atemoya seeds (EEAA) in vitro and in vivo.MethodsThe anti-angiogenic potential of EEAA was evaluated using various in vitro/in vivo models, including cell proliferation, migration, and tube formation by human umbilical vascular endothelial cells (HUVECs); a Matrigel plug assay; and tumor-induced angiogenesis. The expression of hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF) was investigated using reverse transcription-polymerase chain reaction, immunoassays, and western blotting.ResultsEEAA was able to significantly inhibit the angiogenic properties of HUVECs in vitro as well as angiogenic factor-induced blood vessel formation in vivo. EEAA down-regulated the expression of VEGF and HIF-1alpha/2alpha at the mRNA and protein levels, respectively, in cancer cells under hypoxic conditions.ConclusionsEEAA shows a strong anti-angiogenic potential in both in vitro and in vivo systems, and we suggest that EEAA may be a valuable herbal source for anticancer drug development.

Isoliquiritin Apioside Suppresses in vitro Invasiveness and Angiogenesis of Cancer Cells and Endothelial Cells

“…Agents targeting HIF-1α signaling such as EZN-2968 (HIF-1α antisense mRNA) and PX-478 (small molecule inhibitor of HIF-1α) have been effective treatments for advanced solid tumors and lymphoma in phase I clinical trials (Jeong et al, 2014; Welsh et al, 2004). In addition, several phytochemicals, such as curcumin, wogonin, and resveratrol, and herbal medicines, such as an ethanol extract of baked Gardeniae Fructus and an ethanol extract of Annona atemoya , have been reported to have anti-angiogenic effects through inhibition of the HIF-1α pathway (Song et al, 2013; Yi et al, 2014; Bae et al, 2006; Im et al, 2016).…”

The Phytochemical Constituents and Pharmacological Activities of Annona atemoya: A Systematic Review

“…The ethanolic extract of A. atemoya seeds was examined for its anti-angiogenic activity in human umbilical vein endothelial cells (HUVECs). The ethanolic seed extract of A. atemoya elicited a significant dose-dependent inhibition of HUVEC mobility at concentration ≥100 µg/mL without decreasing cell viability [ 12 ]. Using the matrigel plug assay, the ethanol extract at concentration ≥25 µg/mL was also shown to inhibit the formation of new blood vessels in vivo, in a dose-dependent manner.…”

“…Using the matrigel plug assay, the ethanol extract at concentration ≥25 µg/mL was also shown to inhibit the formation of new blood vessels in vivo, in a dose-dependent manner. Further investigation indicated that under hypoxic conditions the extract down-regulated the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF-1alpha/2alpha) [ 12 ]. These results indicate that the extract modulated angiogenesis both directly through the endothelial cells and indirectly though modulating the tumour-induced angiogenic pathways [ 12 ].…”

“…As a relatively recent hybrid, traditional uses of A. atemoya are lacking, with some limited anecdotal evidence that the leaves of A. atemoya are purchased from growers for making teas. Several phytochemical constituents have been isolated from different parts of the A. atemoya plant and assessed for their biological potential in both vivo and vitro studies [ 9 , 10 , 11 , 12 ]. The leaves, fruits and seeds of A. atemoya are the most widely studied for their chemical and pharmacological properties.…”

Cytotoxic and genotoxic effects of extracts fromAnnona montanaM. fruit

“…The Annona muricata L. extract was found to induce apoptosis through a mitochondria-mediated pathway in human cancer cells via upregulation of BAX and downregulation of BCL2 proteins and involvement of nuclear factor-kappa B transcription factor, as indicated by Pieme et al (2014), Moghadamtousi, Kadir, Paydar, Rouhollahi, & Karimian (2014) and Asare et al (2015). The ethanol extract of Annona atemoya seeds was shown to exhibit anti-angiogenic activity by dowregulating the expression of vascular endothelial growth factor and hypoxia-inducible transcription factors (HIF-1 alpha and HIF-2 alpha) in vitro and in vivo (Yi et al, 2014). Similarly, the flavonoid content in Annona dioica St. Hill reportedly exhibited antiproliferative, hypoglycemic, anti-inflammatory and free radical scavenging activities (Formagio et al, 2013).…”