Anti-angiogenic activity of macrolactin A and its succinyl derivative is mediated through inhibition of class I PI3K activity and its signaling

Title
Anti-angiogenic activity of macrolactin A and its succinyl derivative is mediated through inhibition of class I PI3K activity and its signaling
Author(s)
김정애강유라렉미수실김미영수리드반스코타자야가우탐김동희[김동희]
Keywords
TUMOR-NECROSIS-FACTOR; ENDOTHELIAL GROWTH-FACTOR; EMBRYO CHORIOALLANTOIC MEMBRANE; PHOSPHATIDYLINOSITOL 3-KINASE; NADPH OXIDASE; OXIDATIVE STRESS; PHOSPHOINOSITIDE 3-KINASE; NEUTROPHIL TRAFFICKING; NAD(P)H OXIDASE; KINASE-ACTIVITY
Issue Date
201502
Publisher
PHARMACEUTICAL SOC KOREA
Citation
ARCHIVES OF PHARMACAL RESEARCH, v.38, no.2, pp.249 - 260
Abstract
In the current study, macrolactin compounds, macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), were investigated for their anti-angiogenic activities and action mechanism. MA and SMA inhibited in vitro and in vivo angiogenesis induced by three different classes of pro-angiogenic factors, VEGF, IL-8, and TNF-alpha. SMA exhibited stronger anti-angiogenic activity than MA, and such anti-angiogenic activity of SMA was consistently observed in MDA-MB-231 human breast cancer cell-inoculated CAM assay showing dose-dependent suppression of tumor growth and tumor-induced angiogenesis. In an in vitro PI3K competitive activity assay, SMA induced concentration-dependent inhibition of class I PI3K isoforms, p110 alpha, p110 beta, p110 delta, and p110 gamma. In addition, non-receptor tyrosine kinase c-Src, which is involved in the activation of PI3K heterodimer, was suppressed by MA and SMA. Correspondingly, MA and SMA significantly inhibited the stimulus-induced phosphorylation of Akt, mTOR, p70S6K, and ribosomal S6 in human umbilical vein endothelial cells (HUVECs). At the same time, the stimulus-induced production of reactive oxygen species (ROS) and activation of NF-kappa B were significantly suppressed by MA and SMA. Moreover, the macrolactins suppressed NF-kappa B-regulated HSP90 protein expression, which stabilizes phosphorylated Akt and NADPH oxidase. Suppression of NF-kappa B in macrolactin-treated HUVECs with concurrent inhibition of rS6 indicates that MAs effectively block angiogenesis through down-regulation of genes related to angiogenesis at both transcriptional and translational levels. Taken together, the results demonstrate that anti-angiogenic effect of MA and SMA is mediated through inhibition of PI3K/Akt and NADPH oxidase-derived ROS/NF-kappa B signaling pathways. These results further indicate that MA and SMA may be applicable for treatment of various diseases associated with angiogenesis.
URI
http://hdl.handle.net/YU.REPOSITORY/33488http://dx.doi.org/10.1007/s12272-014-0535-x
ISSN
0253-6269
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약학대학 > 약학부 > Articles
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