Natural compounds as potential treatments of NF2-deficient schwannoma and meningioma: cucurbitacin D and goyazensolide.
OBJECTIVE
Cucurbitacin D and goyazensolide, 2 plant-derived natural compounds, possess potent growth-inhibitory activity in schwannoma and meningioma cells.


BACKGROUND
Currently, no FDA-approved drugs are available for neurofibromatosis type 2 (NF2)-associated schwannomas and meningiomas. Selected natural compounds with antineoplastic activity, such as cucurbitacin D and goyazensolide, may be developed as potential treatments for these tumors.


METHODS
The Nf2-deficient mouse schwannoma Sch10545 and human benign meningioma Ben-Men-1 cells were treated with various concentrations of cucurbitacin D and goyazensolide. The effect on cell proliferation was determined using resazurin assays. Flow cytometry was used to assess the cell cycle profiles. Western blot analysis was performed to investigate the expression of various signaling molecules related to the cell cycle and the AKT pathway.


RESULTS
Cucurbitacin D inhibited proliferation of Sch10545 cells (IC50 ∼ 0.75 μM) and Ben-Men-1 cells (IC50 ∼0.2 μM). Goyazensolide also reduced cell proliferation of Sch10545 cells (IC50 ∼0.9 μM) and Ben-Men-1 cells (IC50 ∼1 μM). The G2/M population increased in both Sch10545 and Ben-Men-1 cells treated with cucurbitacin D or goyazensolide around the IC50. Cucurbitacin and goyazensolide substantially reduced the levels of cyclins E and A in treated Sch10545 and Ben-Men-1 cells. Cucurbitacin D also inhibited cyclin B, phospho-AKT and phospho-PRAS40 expression. In addition, goyazensolide reduced the levels of phospho-AKT and NFκB and increased the expression of pro-apoptotic Bim in Sch10545 and Ben-Men-1 cells.


CONCLUSIONS
Both cucurbitacin D and goyazensolide effectively inhibit proliferation of NF2-deficient schwannoma and meningioma cells, suggesting that these natural compounds should be further evaluated as potential treatments for NF2-related tumors.
*Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital; †Departments of Otolaryngology, ‡Pediatrics, The Ohio State University College of Medicine; and §Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio, U.S.A.
Samuel A
SA
Spear
Sarah S
SS
Burns
Janet L
JL
Oblinger
Yulin
Y
Ren
Li
L
Pan
A Douglas
AD
Kinghorn
D Bradley
DB
Welling
Long-Sheng
LS
Chang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D056945:Hep G2 Cells; D006801:Humans; D008577:Meningeal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008579:Meningioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009442:Neurilemmoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D025581:Neurofibromin 2 / Q000378:metabolism; D054830:Sesterterpenes; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D005663:Furans; D025581:Neurofibromin 2; D054830:Sesterterpenes; D014315:Triterpenes; C499803:furanoheliangolide; C038105:cucurbitacin D