Abstract
BackgroundCurrently, 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.MethodsPrimary 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.ResultsCerebrospinal 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.ConclusionsThese 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.
Highlights
There are no consistently effective chemotherapies for recurrent and inoperable meningiomas
To characterize cucurbitacin I, we evaluated its effects on proliferation and growth regulatory pathways in numerous human leptomeningeal, grade I and II meningioma cell cultures
Meningioma cell cultures were plated onto 2 well microscope slides (Nalgene NUNC Int., Rochester, NY) for 1 day in DMEM with 10% fetal bovine serum (FBS) fixed in formalin
Summary
There are no consistently effective chemotherapies for recurrent and inoperable meningiomas. The lack of effective chemotherapies compromises management of recurrent or inoperable meningiomas [1,2]. 12% of intracranial world health organization (WHO) grade I meningiomas recur within 5 years of gross total resection [3,4]. Recurrence rates of skull base meningiomas are even higher [7,8]. In these cases effective chemotherapies have not been established and recent promising treatments have proven suboptimal [9,10,11,12]. In a recent study of Gamma Knife-treated skull base meningiomas, followed for up to 103 months, 33% exhibited variable regression, 64% were stabilized and 6% showed progression [15]. Radiotherapy as an initial treatment was less effective in large meningiomas greater than 5 cm3 [16]
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