title: Use of a glycolipid inhibitor to ameliorate renal cancer in a mouse model.
abstract: In a xenograft model wherein, live renal cancer cells were implanted under the kidney capsule in mice, revealed a 30-fold increase in tumor volume over a period of 26 days and this was accompanied with a 32-fold increase in the level of lactosylceramide (LacCer). Mice fed D- threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of glucosylceramide synthase and lactosylceramide synthase (LCS: β-1,4-GalT-V), showed marked reduction in tumor volume. This was accompanied by a decrease in the mass of lactosylceramide and an increase in glucosylceramide (GlcCer) level. Mechanistic studies revealed that D-PDMP inhibited cell proliferation and angiogenesis by inhibiting p44MAPK, p-AKT-1 pathway and mammalian target for rapamycin (mTOR). By linking glycosphingolipid synthesis with tumor growth, renal cancer progression and regression can be evaluated. Thus inhibiting glycosphingolipid synthesis can be a bonafide target to prevent the progression of other types of cancer.
authors.affiliation: Department of Pediatrics, Division of Pediatric Cardiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. schatte2@jhmi.edu
authors.forename: Subroto
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Nezar
authors.initials: N
authors.lastname: Alsaeedi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hou
authors.forename: Veera Venkata Ratnam
authors.initials: VV
authors.lastname: Bandaru
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.forename: Georges
authors.initials: G
authors.lastname: Ndikuyeze
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Haughey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015153:Blotting, Western; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005963:Glucosylceramides / Q000378:metabolism; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007790:Lactosylceramides / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D007790:Lactosylceramides; D009025:Morpholines; D010446:Peptide Fragments; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C503486:WDR77 protein, mouse; C009744:CDw17 antigen; C033110:RV 538; D005700:Galactosyltransferases; D005964:Glucosyltransferases; C039090:UDPgalactose-glucosylceramide galactosyltransferase; C023246:ceramide glucosyltransferase; D051057:Proto-Oncogene Proteins c-akt