Arenobufagin activates p53 to trigger esophageal squamous cell carcinoma cell apoptosis in vitro and in vivo
نویسندگان
چکیده
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 μM to 3.6 μM. 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.
منابع مشابه
Induction of Apoptosis by a Combination of 2-Deoxyglucose and Metformin in Esophageal Squamous Cell Carcinoma by Targeting Cancer Cell Metabolism
Background: Both mitochondrial dysfunction and aerobic glycolysis are signs of growing aggressive cancer. If altered metabolism of cancer cell is intended, using the glycolysis inhibitor (2-deoxyglucose (2DG)) would be a viable therapeutic method. The AMP-activated protein kinase (AMPK), as a metabolic sensor, could be activated with metformin and it can also launch a p53-dependent metabolic ch...
متن کاملThe Effect Of P53 Protein Over-Expression And Its Clinical Features On The Response To Preoperative Chemoradiotherapy Of Esophageal Squamous Cell Carcinoma
Background and Objective: P53 is a suppressive gene that plays a key role in DNA repair and apoptosis. The purpose of this study was to investigate the effect of P53 protein over-expression and some clinicopathological factors on the esophageal squamous cell carcinoma (SCC) response to neoadjuvant chemoradiotherapy. Patients and Methods: In this retrospective cohort study, 44 patients with loc...
متن کاملMutations of p53 Gene in Skin Cancers: a Case Control Study
Background: The most frequently mutated tumor suppressor gene found in human cancer is p53. In a normal situation, p53 is activated upon the induction of DNA damage to either arrest the cell cycle or to induce apoptosis. However, when mutated, p53 is no longer able to properly accomplish these functions. The aim of this study was to investigate the expression of p53 gene in cases of skin cancer...
متن کاملIdentification of p53 Gene Mutations among Iranian Patients Involved with Esophageal Squamous Cell Carcinoma: the Efficiency of the Two Different Methods
متن کامل
ژنتیک مولکولی و ژن درمانی در سرطان مری: مقاله مروری
Background: With approximately 386,000 deaths per year, esophageal cancer is the 6th most common cause of death due to cancer in the world. This cancer, like any other cancer, is the outcome of genetic alterations or environmental factors such as tobacco smoke and gastro-esophageal reflux. Tobacco smoking is a major etiologic factor for esophageal squamous cell carcinoma in western countries, a...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 10 شماره
صفحات -
تاریخ انتشار 2017