title: NT1014, a novel biguanide, inhibits ovarian cancer growth in vitro and in vivo.
abstract: BACKGROUND
  NT1014 is a novel biguanide and AMPK activator with a high affinity for the organic cation-specific transporters, OCT1 and OCT3. We sought to determine the anti-tumorigenic effects of NT1014 in human ovarian cancer cell lines as well as in a genetically engineered mouse model of high-grade serous ovarian cancer.
  
  
  METHODS
  The effects of NT1014 and metformin on cell proliferation were assessed by MTT assay using the human ovarian cancer cell lines, SKOV3 and IGROV1, as well as in primary cultures. In addition, the impact of NT1014 on cell cycle progression, apoptosis, cellular stress, adhesion, invasion, glycolysis, and AMPK activation/mTOR pathway inhibition was also explored. The effects of NT1014 treatment in vivo was evaluated using the K18 - gT121+/-; p53fl/fl; Brca1fl/fl(KpB) mouse model of high-grade serous ovarian cancer.
  
  
  RESULTS
  NT1014 significantly inhibited cell proliferation in both ovarian cancer cell lines as well as in primary cultures. In addition, NT1014 activated AMPK, inhibited downstream targets of the mTOR pathway, induced G1 cell cycle arrest/apoptosis/cellular stress, altered glycolysis, and reduced invasion/adhesion. Similar to its anti-tumorigenic effects in vitro, NT1014 decreased ovarian cancer growth in the KpB mouse model of ovarian cancer. NT1014 appeared to be more potent than metformin in both our in vitro and in vivo studies.
  
  
  CONCLUSIONS
  NT1014 inhibited ovarian cancer cell growth in vitro and in vivo, with greater efficacy than the traditional biguanide, metformin. These results support further development of NT1014 as a useful therapeutic approach for the treatment of ovarian cancer.
authors.affiliation: Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, People's Republic of China.|Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.|Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Jinan, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Han
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Jackson
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Leslie N
authors.initials: LN
authors.lastname: Clark
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Kilgore
authors.affiliation: Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, People's Republic of China.|Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.|School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: NovaTarg Therapeutics, Research Triangle Park, Durham, NC, 27709, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Livingston
authors.affiliation: NovaTarg Therapeutics, Research Triangle Park, Durham, NC, 27709, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Batchelor
authors.affiliation: Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, People's Republic of China.|Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.|School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, People's Republic of China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Gilliam
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Paola A
authors.initials: PA
authors.lastname: Gehrig
authors.affiliation: Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, People's Republic of China.
authors.forename: Xiugui
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA. czhou@med.unc.edu.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. czhou@med.unc.edu.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA. victoria_baejump@med.unc.edu.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. victoria_baejump@med.unc.edu.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bae-Jump
keywords: AMPK; Biguanide; NT1014; Ovarian cancer; Small compound