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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Angiogenesis
2015 ; 18
(3
): 283-99
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AECHL-1, a novel triterpenoid, targets tumor neo-vasculature and impairs the
endothelial cell cytoskeleton
#MMPMID25952529
Dasgupta A
; Sawant MA
; Lavhale MS
; Krishnapati LS
; Ghaskadbi S
; Sitasawad SL
Angiogenesis
2015[Jul]; 18
(3
): 283-99
PMID25952529
show ga
Tumor angiogenesis is characterized by abnormal vessel morphology leading to
erratic and insufficient delivery of chemotherapeutics and oxygen, making the
tumor core not only highly hypoxic but also unresponsive toward treatment. Such
hypoxic conditions promote tumor aggressiveness, leading to the establishment of
metastatic disease. Most anti-angiogenic treatments aim toward the destruction of
tumor vasculature, which proves countereffective by further increasing its
aggressive nature. Hence, developing drugs which target or regulate these
processes might lead to a better delivery of chemotherapeutics resulting in tumor
shrinkage. Plant-derived natural compounds having a bioactive ingredient,
especially triterpenoids, have been known to possess anticancer properties.
AECHL-1, a recently isolated novel triterpenoid with proven anticancer potential,
is seemingly noncytotoxic toward HEK 293 and HUVECs. Also, cytotoxicity was
absent during in vivo studies involving intraperitoneal injections with 5 µg/kg
body weight AECHL-1 on SCID mice. When used at subtoxic doses, it was found to be
effective in suppression of neo-vessel formation as demonstrated in the chick
chorioallantoic membrane, rat aortic rings, Matrigel plugs and xenograft tumors
implanted in SCID mice. Tumor vasculature from AECHL-1-treated mice showed
greater mural cell coverage and relatively normalized architecture.
Investigations into the molecular mechanisms responsible for these observations
revealed an effect on the actin cytoskeleton of stimulated HUVECs as well as the
VEGFR2-mediated MAPK pathway. AECHL-1 could effectively distinguish between
stimulated and nonstimulated endothelial cells. AECHL-1 could also downregulate
HIF-1? expression and VEGF secretion under hypoxic conditions, thus reducing the
fears of unnecessarily aggravating tumor metastasis as a result of
anti-angiogenic therapy. Results obtained from the aforementioned studies make it
clear that though AECHL-1 shows promise in discouraging and pruning
neo-vasculature, it may not affect existing vasculature as the doses used for the
assays are significantly lower than the ones causing endothelial cell death and
has potential to be considered as a candidate for therapeutic drug development.
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