title: Inhibition of sphingosine kinase-2 ablates androgen resistant prostate cancer proliferation and survival.
abstract: BACKGROUND
  Endogenous sphingolipid signaling has been shown to play an important role in prostate cancer endocrine resistance.
  
  
  METHODS
  The novel SphK2 inhibitor, ABC294640, was used to explore SphK signaling in androgen resistant prostate cancer cell death signaling.
  
  
  RESULTS
  It dose-dependently decreased PC-3 and LNCaP cell viability, IC(50) of 28 ± 6.1 μM (p < 0.05) and 25 ± 4.0 μM (p < 0.05), respectively. ABC294640 was more potent in long-term clonogenic survival assays; IC(50) of 14 ± 0.4 μM (p < 0.05) in PC-3 cells and 12 ± 0.9 μM (p < 0.05) in LNCaP cells. Intrinsic apoptotic assays failed to demonstrate increased caspase-9 activity. Ki-67 staining demonstrated decreased proliferation by 50 ± 8.4% (p < 0.01) in PC-3 cells.
  
  
  CONCLUSIONS
  SphK2 inhibition decreases androgen resistant prostate cancer viability, survival, and proliferation independently of the intrinsic apoptotic pathway. Findings are in contrast to recent observations of ABC29460 acting dependently on the intrinsic pathway in other endocrine resistant cancer cell lines.
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Gestaut
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Antoon
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA. Electronic address: bbeckman@tulane.edu.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Beckman
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000726:Androgen Antagonists / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000502:physiology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D000099157:Sphingosine Kinase
chemical_list: D000218:Adamantane; D000726:Androgen Antagonists; D019394:Ki-67 Antigen; D017853:Phosphotransferases (Alcohol Group Acceptor); D011725:Pyridines; D000099157:Sphingosine Kinase; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
keywords: Chemoresistance; Prostate cancer; Sphingolipids; Sphingosine kinase; Sphingosine kinase 2