title: Cucurbitacin I blocks cerebrospinal fluid and platelet derived growth factor-BB stimulation of leptomeningeal and meningioma DNA synthesis.
abstract: BACKGROUND
  Currently, there are no consistently effective chemotherapies for recurrent and inoperable meningiomas. Recently, cucurbitacin I (JSI-124), a naturally occurring tetracyclic triterpenoid compound used as folk medicines has been found to have cytoxic and anti-proliferative properties in several malignancies thru inhibition of activator of transcription (STAT3) activation. Previously, we have found STAT3 to be activated in meningiomas, particularly higher grade tumors.
  
  
  METHODS
  Primary leptomeningeal cultures were established from 17, 20 and 22 week human fetuses and meningioma cell cultures were established from 6 World Health Organization (WHO) grade I or II meningiomas. Cells were treated with cerebrospinal fluid from patients without neurologic disease. The effects of cucurbitacin I on cerebrospinal fluid stimulation of meningioma cell DNA synthesis phosphorylation/activation of JAK1, STAT3, pMEK1/2, p44/42MAPK, Akt, mTOR, Rb and caspase 3 activation were analyzed in human leptomeningeal and meningioma cells.
  
  
  RESULTS
  Cerebrospinal fluid significantly stimulated DNA synthesis in leptomeningeal cells. Co-administration of cucurbitacin I (250 nM) produces a significant blockade of this effect. Cucurbitacin I alone also produced a significant reduction in basal DNA synthesis. In grade I and II meningiomas, cerebrospinal fluid also significantly stimulated DNA synthesis. Co-administration of cucurbitacin I (250 nM) blocked this effect.In the leptomeningeal cultures, cerebrospinal fluid stimulated STAT3 phosphorylation but not p44/42MAPK, Akt or mTOR. Cucurbitacin I had no effect on basal STAT3 phosphorylation but co-administration with cerebrospinal fluid blocked cerebrospinal fluid stimulation of STAT3 phosphorylation in each. In the grade I meningiomas, cerebrospinal fluid stimulated phosphorylation of STAT3 and decreased MEK1/2 and cucurbitacin I had no effect on basal STAT3, p44/42MAPK, Akt, JAK1, mTOR, or Rb phosphorylation. In the grade II meningiomas, cerebrospinal fluid stimulated STAT3 phosphorylation in all and reduced phosphorylation of MEK1/2 in all and p44/42MAPK in one. Cucurbitacin I had no effect on basal phosphorylation of STAT3 but reduced phorphorylated p44/42 MAPK in 2 grade II meningioma cells lines.
  
  
  CONCLUSIONS
  These studies raise the possibility that cucurbitacin I might have value as an adjunct chemotherapy. Additional studies are warranted to evaluate the effects of cucurbitacin I on meningiomas in vivo.
authors.affiliation: Division of Neuropathology, Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Box 626, 601 Elmwood Ave,, Rochester, NY 14642, USA. mahlon_johnson@urmc.rochester.edu.
authors.forename: Mahlon D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Mary J
authors.initials: MJ
authors.lastname: O'Connell
authors.forename: Kevin
authors.initials: K
authors.lastname: Walter
mesh_terms: D000328:Adult; D000368:Aged; D000077214:Becaplermin; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008577:Meningeal Neoplasms / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008579:Meningioma / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D050796:STAT3 Transcription Factor; D014315:Triterpenes; D000077214:Becaplermin; D004247:DNA; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C038106:cucurbitacin I