title: Inhibition of phosphodiestrase 9 induces cGMP accumulation and apoptosis in human breast cancer cell lines, MCF-7 and MDA-MB-468.
abstract: OBJECTIVE
  Phosphodiesterase 9 (PDE9) is a major isoform of phosphodiesterase hydrolysing cGMP and plays a key role in proliferation of cells, their differentiation and apoptosis, via intracellular cGMP signalling. The study described here was designed to investigate expression, activity and apoptotic effect of PDE9 on human breast cancer cell lines, MCF-7 and MDA-MB-468.
  
  
  METHODS
  Activity and expression of PDE9 were examined using colorimetric cyclic nucleotide phosphodiesterase assay and real-time RT-PCR methods respectively; cGMP concentration was also measured. MTT viability test, annexin V-FITC staining, Hoechst 33258 staining and caspase3 activity assay were used to detect apoptosis.
  
  
  RESULTS
  Treatment of both cell lines with BAY 73-6691 lead to reduction in PDE9 mRNA expression, PDE9 cGMP-hydrolytic activity and elevation of the intracellular cGMP response. BAY 73-6691 significantly reduced cell proliferation in a dose- and time-dependent manner and caused marked increase in apoptosis through caspase3 activation.
  
  
  CONCLUSIONS
  Our results revealed that BAY 73-6691 induced apoptosis in these breast cancer cell lines through the cGMP pathway. These data suggest that BAY 73-6691 could be utilized as an agent in treatment of breast cancer.
authors.affiliation: Clinical Biochemistry Department, School of Medical Science, Tarbiat Modares University, Tehran, Iran.
authors.forename: R
authors.initials: R
authors.lastname: Saravani
authors.forename: F
authors.initials: F
authors.lastname: Karami-Tehrani
authors.forename: M
authors.initials: M
authors.lastname: Hashemi
authors.forename: M
authors.initials: M
authors.lastname: Aghaei
authors.forename: R
authors.initials: R
authors.lastname: Edalat
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: C507056:BAY 73-6691; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C116137:PDE9A protein, human; D053148:Caspase 3; D006152:Cyclic GMP