AT101 exerts a synergetic efficacy in gastric cancer patients with 5-FU based treatment through promoting apoptosis and autophagy

• Published in: Oncotarget Vol. 7; no. 23; pp. 34430 - 34441
• Main Authors: Wei, Xi, Duan, Wei, Li, Ying, Zhang, Sheng, Xin, Xiaojie, Sun, Lei, Gao, Ming, Li, Qing, Wang, Dong
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 07.06.2016
• Subjects: AC133 Antigen - antagonists & inhibitors; Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Autophagy - drug effects; Cell Line, Tumor; Cell Movement - drug effects; DNA-(Apurinic or Apyrimidinic Site) Lyase - antagonists & inhibitors; Drug Synergism; Female; Fluorouracil - pharmacology; Gossypol - analogs & derivatives; Gossypol - pharmacology; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Microtubule-Associated Proteins - antagonists & inhibitors; Middle Aged; Nanog Homeobox Protein - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Research Paper; Stomach Neoplasms - drug therapy; Xenograft Model Antitumor Assays; gastric cancer; APE1; AT101; Her-2 positive; 5-FU
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.9119

Gastric cancer remains a disease with a high mortality rate despite of multiple therapeutic strategies. So far, it is very important to develop new treatment approaches to improve current therapeutic efficacy in gastric cancer. Apurinic/apyrimidinic endonuclease (APE1) involves in DNA base excision repair (BER) during DNA damage pathway. APE1 was found to be associated with poor overall survival with gastric cancer patients. In the in vitro experiment, we tested APE1 inhibitor-AT101 could potently inhibit gastric cancer cell growth and further induce cancer cell apoptosis and autophagy through p53-dependent pathway. Downregulation of APE1 by AT101 has ability to suppress gastric cancer cell migration and renewal through inhibition of CD133, Nanog and LC3expression. Based on findings that Her-2 positive expression cases has poor prognosis from our dataset and TCGA database, we investigated the role of AT101 in synergetic efficacy with 5-FU treatment in Her-2 overexpression gastric cancer in vivo, indicating that AT101 is able to enhance 5-FU in the shrinkage of xenograft mice tumor and induction of cell apoptosis. In summary, the data obtained from our study showed APE1 is guided as a potential therapeutic target for gastric cancer. AT101 could be regarded as a potent inhibitor to promote chemotherapeutic sensitivity in patients with gastric cancer.