Cucurbitacin I blocks cerebrospinal fluid and platelet derived growth factor-BB stimulation of leptomeningeal and meningioma DNA synthesis

Mahlon Johnson, Mary J. O'Connell, Kevin Walter

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article number303
JournalBMC Complementary and Alternative Medicine
Volume13
DOIs
StatePublished - Nov 4 2013

Fingerprint

Meningioma
Cerebrospinal Fluid
Phosphorylation
DNA
platelet-derived growth factor BB
cucurbitacin I
Drug Therapy
Mitogen-Activated Protein Kinase 3
Traditional Medicine
Nervous System Diseases
Caspase 3
Transcriptional Activation
Neoplasms
Fetus
Cell Culture Techniques
Cell Line

All Science Journal Classification (ASJC) codes

  • Complementary and alternative medicine

Cite this

@article{1e669c34631d423a89312a859f722b83,
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.",
author = "Mahlon Johnson and O'Connell, {Mary J.} and Kevin Walter",
year = "2013",
month = "11",
day = "4",
doi = "10.1186/1472-6882-13-303",
language = "English (US)",
volume = "13",
journal = "BMC Complementary and Alternative Medicine",
issn = "1472-6882",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Cucurbitacin I blocks cerebrospinal fluid and platelet derived growth factor-BB stimulation of leptomeningeal and meningioma DNA synthesis

AU - Johnson, Mahlon

AU - O'Connell, Mary J.

AU - Walter, Kevin

PY - 2013/11/4

Y1 - 2013/11/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84886743300&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886743300&partnerID=8YFLogxK

U2 - 10.1186/1472-6882-13-303

DO - 10.1186/1472-6882-13-303

M3 - Article

VL - 13

JO - BMC Complementary and Alternative Medicine

JF - BMC Complementary and Alternative Medicine

SN - 1472-6882

M1 - 303

ER -