Antiproliferative effect of peripheral benzodiazepine receptor antagonist PK11195 in rat mammary tumor cells.
This study aims to establish the antiproliferative effects of PK11195, a peripheral benzodiazepine receptor antagonist (PBR) in rat mammary tumor cells. Breast tumors were induced by administration of a carcinogen, dimethylbenz[a]anthracene to 50-day-old female rats maintained on a standard AIN-76A diet with casein as the protein source. The tumors were developed approximately after 120 days. The tumors were of grade I (20%), grade II (60%), and grade III (20%). The tumors were isolated and cultured in DMEM/F12 media with supplements. We characterized the properties of the isolated cells and study the effect of PK11195 on those cells. We were successful in growing breast tumor cells up to 30 passages for cellular characterization. These cells had high reactivity with Ki-67 and PCNA antibodies suggesting high proliferation rate. These cells were highly invasive as evident by matrigel invading ability. Furthermore, these cells acquired a positive response for CD-31 and VEGF antibodies suggesting angiogenic potential, and also possessed migrating ability/motility as evident by the wound healing properties. These cells expressed elevated levels of PBR, a cancer promoting gene. The proliferation, invasion and migration appear to decrease when treated with PK11195, a PBR antagonist. Furthermore, PK11195 treatment caused an increase in apoptosis as evident by increase in the levels of annexin V. However, the inhibition of cell proliferation by PK11195 was counteracted by Ro5-4864, a PBR agonist. Thus, PBR antagonist may be a potential therapeutic agent for the control of aggressiveness of breast cancer.
Mukhopadhyay
Sutapa
S
Department of Cancer Biology, Meharry Medical College, 1005 D.B.Todd Blvd., Nashville, TN 37208, USA.
Guillory
Bobby
B
Mukherjee
Shyamali
S
Das
Salil K
SK
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001570:Benzodiazepinones / Q000494:pharmacology; D002352:Carrier Proteins / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines / Q000494:pharmacology*; D019394:Ki-67 Antigen / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D017304:Annexin A5; D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D002352:Carrier Proteins; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines; D019394:Ki-67 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D011963:Receptors, GABA-A; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C069997:Tspo protein, rat; C028513:4'-chlorodiazepam; D015127:9,10-Dimethyl-1,2-benzanthracene; C037850:PK 11195