title: The Akt inhibitor ISC-4 activates prostate apoptosis response protein-4 and reduces colon tumor growth in a nude mouse model.
abstract: OBJECTIVE
  Prostate apoptosis response protein-4 (Par-4) sensitizes cells to chemotherapy; however, Akt1 inactivates Par-4. Previously we showed that Par-4-overexpressing colon cancer cells responded more readily to 5-fluorouracil (5-FU) than their wild-type counterparts. In this study we investigated (i) the effects of the Akt inhibitor, phenylbutyl isoselenocyanate (ISC-4), on tumor growth in nude mice and (ii) bystander effect of Par-4-overexpressing cells on wild-type tumor growth.
  
  
  METHODS
  Mice (n = 80) were injected with wild-type HT29 human colon cancer cells in the right flank. Forty of the mice were also injected in the left flank with HT29 cells engineered to overexpress Par-4. The mice were treated with 5-FU, ISC-4, a combination, or vehicle.
  
  
  RESULTS
  ISC-4 reduced tumor growth, with or without 5-FU. When Par-4-overexpressing tumors were present, wild-type tumors grew more slowly compared to when no Par-4-overexpressing tumors were present. The level of Par-4 protein as well as the Par-4 binding protein, GRP78, was increased in wild-type cells growing in the same mouse as Par-4-overexpressing tumors compared with wild-type tumors growing without Par-4-overexpressing tumors.
  
  
  CONCLUSIONS
  Par-4-overexpressing tumors exhibited a bystander effect on wild-type tumors growing distally in the same mouse. This suggests that gene therapy need not achieve total penetration to have a positive effect on tumor treatment. Inhibition of Akt with ISC-4 inhibited tumor growth and had a greater effect on cells overexpressing Par-4. The data indicate ISC-4 alone or in combination with Par-4 can greatly reduce tumor growth.
authors.affiliation: Department of Pharmacology, Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Christina L
authors.initials: CL
authors.lastname: Kline
authors.forename: Arthur
authors.initials: A
authors.lastname: Berg
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Rosalyn B
authors.initials: RB
authors.lastname: Irby
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D024201:Bystander Effect / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016566:Organoselenium Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C561852:ISC-4 compound; D016566:Organoselenium Compounds; D047428:Protein Kinase Inhibitors; C101296:prostate apoptosis response-4 protein; D051057:Proto-Oncogene Proteins c-akt