title: A novel AMPK activator reduces glucose uptake and inhibits tumor progression in a mouse xenograft model of colorectal cancer.
abstract: The anticancer activity of a novel pure 1,4-Diaryl-2-azetidinone (1), endowed with a higher solubility than the well known Combretastatin A4, is tested in mice. We previously reported that Compound (1) showed specific antiproliferative activity against duodenal and colon cancer cells, inducing activation of AMP-activated protein kinase and apoptosis. Here we estimate that the maximum tolerated dose in a mouse model is 40 mg/kg; the drug is well tolerated both in single dose and in repeated administration schedules. The drug displays a significant antitumor activity and a tumor growth delay when administered at the MTD both in single and fractionated i.v. administration in a mouse xenograft model of colorectal cancer. Arrest of tumor growth and relapse after drug suspension are parallel to modification in glucose demand as shown by PET studies with [(18)F] FDG. These data strongly support Compound (1) as a promising molecule for in vivo treatment of colorectal cancer.
authors.affiliation: IBFM-CNR, Segrate, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Valtorta
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nicolini
authors.forename: Farida
authors.initials: F
authors.lastname: Tripodi
authors.forename: Cristina
authors.initials: C
authors.lastname: Meregalli
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.forename: Federica
authors.initials: F
authors.lastname: Avezza
authors.forename: Luca
authors.initials: L
authors.lastname: Crippa
authors.forename: Gloria
authors.initials: G
authors.lastname: Bertoli
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Paola
authors.initials: P
authors.lastname: Fusi
authors.forename: Roberto
authors.initials: R
authors.lastname: Pagliarin
authors.forename: Fulvia
authors.initials: F
authors.lastname: Orsini
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Moresco
authors.forename: Paola
authors.initials: P
authors.lastname: Coccetti
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001384:Azetidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D023041:Xenograft Model Antitumor Assays
chemical_list: C000599294:3-hydroxy-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one; D000970:Antineoplastic Agents; D001384:Azetidines; D006139:Guaiacol; D055372:AMP-Activated Protein Kinases; D005947:Glucose