title: Anacardic acid induces caspase-independent apoptosis and radiosensitizes pituitary adenoma cells.
abstract: OBJECTIVE
  Pituitary adenomas, which are common intracranial tumors, are associated with significant patient morbidity due to hormone secretion or mass effect or as a complication of therapy. Epigenetic regulation has emerged as an important component of malignant tumor pathogenesis, although the contribution in the progression of benign pituitary tumors remains largely unexplored. The present study evaluates the effect of anacardic acid (6-pentadecyl salicylic acid), a natural histone acetyltransferase inhibitor, on pituitary adenoma cells.
  
  
  METHODS
  The concentration- and time-dependent effects of anacardic acid on the viability of GH3 and MMQ pituitary adenoma cells were determined by 3-(4,5-dimethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle phase distribution, protein expression, and percentage of apoptotic cells were assessed by flow cytometry and Western blotting. Colony forming assays were used to study the radiosensitizing effect of anacardic acid.
  
  
  RESULTS
  The present study identifies a novel antiproliferative and cytotoxic effect of anacardic acid on pituitary adenoma cells. These effects were associated with an increase in poly([adenosine diphosphate]-ribose) polymerase cleavage, sub-G1 arrest, and annexin V staining, consistent with apoptotic cell death; however, the pancaspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-(O-methyl)-fluoromethylketone failed to reverse anacardic acid-induced cell death, suggesting a possible nonclassical apoptotic mechanism. Anacardic acid also reduced the expression of survivin and X-linked inhibitor of apoptosis protein, antiapoptotic proteins associated with cellular survival and radioresistance, and radiosensitized pituitary adenoma cells.
  
  
  CONCLUSIONS
  These findings warrant further exploration of anacardic acid as a single agent or as an adjunct to radiation therapy for the treatment of pituitary tumors.
authors.affiliation: Department of Neurosurgery, Medical College of Georgia, Augusta, Georgia 30809, USA.
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Sukumari-Ramesh
authors.forename: Nagendra
authors.initials: N
authors.lastname: Singh
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jensen
authors.forename: Krishnan M
authors.initials: KM
authors.lastname: Dhandapani
authors.forename: John R
authors.initials: JR
authors.lastname: Vender
mesh_terms: D048729:Anacardic Acids / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects* / Q000528:radiation effects; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D051379:Mice; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D048729:Anacardic Acids; D011838:Radiation-Sensitizing Agents; D051636:X-Linked Inhibitor of Apoptosis Protein; C088115:anacardic acid