A Novel AMPK Activator, NT1014, Inhibits Cell Proliferation And Tumor Growth In Ovarian Cancer

Metformin is suggested to have the potential in the treatment of ovarian cancer, probably through the AMPK/mTOR/S6 pathway and the activation of organic cation transporters(OCTs). NT1014, a novel biguanide, was designed as a direct AMPK activator with high affinity for OCT1 and OCT3. The aim of our study is to evaluate the effect of NT1014 in ovarian cancer cell lines and a genetically mouse model of serous ovarian cancer. IGROV-1and SKOV3 cells were assayed for cytotoxicity, cell cycle, apoptosis, adhesion, invasion, the expression of OCT1, and changes of AMPK/mTOR/S6. A genetically engineered mouse model of serous ovarian cancer was used to evaluate the antitumor efficacy of NT1014 in vivo. After 4 weeks treatment, tumor weight, level of VEGF and Immunohistochemistry were assayed between two groups. NT1014 significantly inhibited cell growth in two ovarian cancer cell lines in a doses dependent manner, and IC50 values were lower than Metformin treatment. NT1014 treatment caused cell cycle G1 arrest and induced apoptosis, cellular stress,adhesion and invasion. NT1014 also increased glucose uptake and lactate, but exhibit a decrease ATP in SKOV3 and an increase in IGROV-1. In addition, NT1014 treatment at75mg/kg/day for 4 weeks markedly suppressed tumor growth and the level of VEGF. And immunohistochemical analysis showed a decrease in expression of Ki-67, phosphorylated-S6,and MMP9, as well as an increase in phosphorylated-AKT and phosphorylated-AMPK. The results from our study demonstrated that NT1014 has a significant inhibition of ovarian cancer both in vitro and in vivo, possibly through the activation of AMPK/mTOR pathway and great affinity for OCT1 and OCT3, suggesting that NT1014 may be a potential anticancer treatment for ovarian cancer.