A renobufagin activates p53 to trigger esophageal squamous cell carcinoma cell apoptosis in vitro and in vivo
A renobufagin activates p53 to trigger esophageal squamous cell carcinoma cell apoptosis in vitro and in vivo
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DOI：
10.2147/ott.s104767
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发表时间：
2017-01-01
影响因子：
4
通讯作者：
Li, Qiling
中科院分区：
文献类型：
--
作者：
Lv, Junhong;Lin, Shaohuan;Li, Qiling
食管鳞状细胞癌（ESCC）常在晚期才被诊断，且缺乏有效的治疗策略。蟾蜍二烯内酯是从蟾蜍Bufo bufo gargarizans Cantor的皮肤和腮腺毒腺中分离得到的强心甾体化合物，具有新的抗癌活性。然而，有关蟾蜍二烯内酯对食管鳞癌细胞的作用及其作用机制的研究却很少。本研究对蟾蜍二烯内酯类化合物蟾毒灵（Bufalin，Bu）和沙蟾毒精（arenobufagin，ArBu）的体内外抗食管鳞癌活性进行了研究，并对其分子机制进行了初步探讨。结果表明，ArBu对一组5个ESCC细胞显示出比Bu更高的抗癌功效，IC 50值范围为0.8 μ M至3.6 μ M。而ArBu对Het-1A人正常食管鳞状细胞的毒性较低，表明其在癌细胞和正常细胞之间具有很强的选择性。此外，ArBu主要通过内源性和外源性途径激活caspase，有效诱导ESCC细胞凋亡。ESCC细胞的处理还通过增强其磷酸化来显着激活p53信号传导。有趣的是，用p53小干扰RNA转染细胞显著抑制ArBu-induced p53磷酸化和总体凋亡细胞死亡。此外，ArBu还通过激活p53通路抑制肿瘤生长，从而显示出新的体内抗癌功效。总之，这些结果证明了蟾蜍二烯内酯对ESCC的p53靶向治疗潜力。
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 IC50 values ranging from 0.8 mu M to 3.6 mu 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.