Background: NT1014 is a novel biguanide and AMPK activator with a high affinity for the organic cation-specific\ntransporters, OCT1 and OCT3. We sought to determine the anti-tumorigenic effects of NT1014 in human ovarian\ncancer cell lines as well as in a genetically engineered mouse model of high-grade serous ovarian cancer.\nMethods: The effects of NT1014 and metformin on cell proliferation were assessed by MTT assay using the human\novarian cancer cell lines, SKOV3 and IGROV1, as well as in primary cultures. In addition, the impact of NT1014 on\ncell cycle progression, apoptosis, cellular stress, adhesion, invasion, glycolysis, and AMPK activation/mTOR pathway\ninhibition was also explored. The effects of NT1014 treatment in vivo was evaluated using the K18 âË?â?? gT121+/âË?â??; p53fl/\nfl; Brca1fl/fl (KpB) mouse model of high-grade serous ovarian cancer.\nResults: NT1014 significantly inhibited cell proliferation in both ovarian cancer cell lines as well as in primary\ncultures. In addition, NT1014 activated AMPK, inhibited downstream targets of the mTOR pathway, induced G1 cell\ncycle arrest/apoptosis/cellular stress, altered glycolysis, and reduced invasion/adhesion. Similar to its antitumorigenic\neffects in vitro, NT1014 decreased ovarian cancer growth in the KpB mouse model of ovarian cancer.\nNT1014 appeared to be more potent than metformin in both our in vitro and in vivo studies.\nConclusions: NT1014 inhibited ovarian cancer cell growth in vitro and in vivo, with greater efficacy than the\ntraditional biguanide, metformin. These results support further development of NT1014 as a useful therapeutic\napproach for the treatment of ovarian cancer.
Loading....