Abstract
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.
Highlights
Gastric cancer is the main leading cause of cancerrelated death around the world [1]
AT101 showed strong inhibitory effect on gastric cancer cells growth in the cell colony formation experiment (Figure 2C and 2D). These results indicated that AT101 could be a potent inhibitor in treatment of gastric cancer cells in vitro
Gastric cancer patients associate with poor prognosis worldwide, despite of conventional cancer therapies including surgery, radiation and chemotherapy
Summary
Gastric cancer is the main leading cause of cancerrelated death around the world [1]. Advanced gastric cancer undergoes a poor prognosis with a median survival of less than 9 months [2]. The treatment plan within physician’s options includes surgery, chemotherapy, radiation or other anticancer drugs. Despite multiple therapeutic choices, the survival rate of patients with advanced gastric cancer remains poor in last several decades[3]. To facilitate optimal therapeutic strategies for gastric cancer is still a challenge for clinical application. Most of cytotoxicity agents for advanced cancer are related to induce genomic DNA damage. The inhibitors of DNA damage or DNA repair process appear to act as effective treatment for carcinomas[4]
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