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2017 ; 10
(ä): 1261-1267
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Arenobufagin activates p53 to trigger esophageal squamous cell carcinoma cell
apoptosis in vitro and in vivo
#MMPMID28280360
Lv J
; Lin S
; Peng P
; Cai C
; Deng J
; Wang M
; Li X
; Lin R
; Lin Y
; Fang A
; Li Q
Onco Targets Ther
2017[]; 10
(ä): 1261-1267
PMID28280360
show ga
Esophageal squamous cell carcinoma (ESCC) is often diagnosed at late incurable
stage and lacks effective treatment strategy. Bufadienolides are cardiotonic
steroids isolated from the skin and parotid venom glands of the toad Bufo bufo
gargarizans Cantor with novel anticancer activity. However, there is little
information about the effects and action mechanisms of bufadienolides on ESCC
cells. In this study, the in vitro and in vivo anti-ESCC activities of
bufadienolides, including bufalin (Bu) and arenobufagin (ArBu), were examined and
the underlying molecular mechanisms were elucidated. The results showed that ArBu
exhibited higher anticancer efficacy than Bu against a panel of five ESCC cells,
with IC(50) values ranging from 0.8 ?M to 3.6 ?M. However, ArBu showed lower
toxicity toward Het-1A human normal esophageal squamous cells, indicating its
great selectivity between cancer and normal cells. Moreover, ArBu effectively
induced ESCC cell apoptosis mainly by triggering caspase activation through
intrinsic and extrinsic pathways. Treatment of ESCC cells also significantly
activated p53 signaling by enhancing its phosphorylation. Interestingly,
transfection of cells with p53 small interfering RNA significantly inhibited the
ArBu-induced p53 phosphorylation and the overall apoptotic cell death.
Furthermore, ArBu also demonstrated novel in vivo anticancer efficacy by
inhibiting the tumor growth through activation of p53 pathway. Taken together,
these results demonstrate the p53-targeting therapeutic potential of
bufadienolides against ESCC.