title: Characterizing the sphingomyelinase pathway triggered by PRIMA-1 derivatives in lung cancer cells with differing p53 status.
abstract: OBJECTIVE
  Derivatives of PRIMA-1 compound, 8a and 8b have been shown to increase cytotoxicity in lung cancer cells through sphingomyelinase pathways in IR and 8a or 8b co-treated lung cancer cells. The goal of the present study was to further elaborate the molecular mechanism of 8a- or 8b-treated lung cancer cells in order to understand their potential as anti-cancer drugs.
  
  
  METHODS
  Biochemical assays, western blot, flow cytometry and gene array analyses were employed to distinguish these mechanisms.
  
  
  RESULTS
  Herein we demonstrated that 8a and 8b cause apoptosis with S-phase arrest in lung cancer cells by activating neutral sphingomyelinase with ceramide production. 8a induces expression of TNF family genes while 8b induces p53-mediated apoptosis genes. Protein analysis shows an increased expression in caspase 8, bcl-2, bax, caspase 9 and cytochrome c.
  
  
  CONCLUSIONS
  PRIMA-1 derivatives provoke cytotoxicity in lung cancer cells mainly through the neutral sphingomyelinase-dependent apoptosis pathway.
authors: Department of Chemistry and Biochemistry, Konneker Research Laboratories, Ohio University, The Ridges-Ohio University, Athens, OH, U.S.A. eroica.soans@stjude.org.
authors: Eroica
authors: E
authors: Soans
authors: Department of Chemistry and Biochemistry, Konneker Research Laboratories, Ohio University, The Ridges-Ohio University, Athens, OH, U.S.A.
authors: Susan C
authors: SC
authors: Evans
authors: Department of Chemistry and Biochemistry, Konneker Research Laboratories, Ohio University, The Ridges-Ohio University, Athens, OH, U.S.A.
authors: Cynthia
authors: C
authors: Cipolla
authors: Department of Chemistry and Biochemistry, Konneker Research Laboratories, Ohio University, The Ridges-Ohio University, Athens, OH, U.S.A.
authors: Elroy
authors: E
authors: Fernandes
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001372:Aza Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D053148:Caspase 3 / Q000096:biosynthesis / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002518:Ceramides / Q000096:biosynthesis; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002518:Ceramides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D013108:Sphingomyelin Phosphodiesterase; D053148:Caspase 3; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one
keywords: PRIMA-1; Sphingomyelinase; apoptosis; lung cancer; p53