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

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.

Prediction of Lymph Node Metastases in Gastric Cancer by Serum APE1 Expression

“…Peripheral blood examination of APE1 enable to assist lymph node metastases assessment other than imaging evaluation. Our previous study indicated that APE1 inhibitor has synergetic effect to promote 5-FU based therapy in gastric cancer 3. We also search out the TCGA dateset to confirm our findings.…”

“…Our study found that APE1 protein overexpression is associated with poor overall survival of gastric cancer patients 3. In this study, based on our previous results, we aim to explore the relationship between serum APE1 expression and gastric cancer lymph nodes involvement 3. We investigate the role of serum APE1 in further prediction of gastric cancer metastasis and prognosis.…”

“…Serum autoantibodies used as biomarkers are highly stable in blood, such as serum Her-2, serum Helicobacter pylori KatA and AhpC antibodies, for novel biomarkers in gastric cancer 8. Our study found that APE1 protein overexpression is associated with poor overall survival of gastric cancer patients 3. In this study, based on our previous results, we aim to explore the relationship between serum APE1 expression and gastric cancer lymph nodes involvement 3.…”

“…Our previous study indicated that APE1 overexpression was associated with poor prognosis of non-small cell lung cancer and enhanced epithelial-Mesenchymal Transition (EMT) of lung cancer cell in vitro and in vivo 2. Other study also reported that APE1 inhibitor was able to suppress gastric cancer cell migration and invasion in combination with 5-Fu treatment 3. Moreover, APE1 serum protein has been screened as candidate biomarkers for lung cancer in prediction of chemotherapeutic efficacy 4.…”

MicroRNA-765 Enhances the Anti-Angiogenic Effect of CDDP via APE1 in Osteosarcoma

“…An APE1 inhibitor, AT101, was used to enhance 5-Fu treatment in non-small cell lung cancer in one study 20 . APE1 expression regulation has been shown to be involved in treatment of various cancers 5 , 6 , 20 , 21 . APE1 down-regulation increased chemotherapeutic sensitivity of cancer cells 20 , 21 .…”