Bortezomib inhibits nuclear factor-kappaB dependent survival and has potent in vivo activity in mesothelioma.
OBJECTIVE
Purpose of this study has been the assessment of nuclear factor-kappaB (NF-kappaB) as a survival factor in human mesothelial cells (HMC), transformed HMC and malignant mesothelioma (MMe) cells. We aimed at verifying whether the proteasome inhibitor Bortezomib could abrogate NF-kappaB activity in MMe cells, leading to tumor cell death and may be established as a novel treatment for this aggressive neoplasm.


METHODS
In HMC and MMe cells, NF-kappaB nuclear translocation and DNA binding were studied by electrophoretic mobility shift assay, following treatment with tumor necrosis factor-alpha (TNF-alpha). The IKK inhibitor Bay11-7082 was also tested to evaluate its effects on HMC, transformed HMC, and MMe cell viability upon exposure to asbestos fibers. Following Bortezomib treatment, cytotoxicity of MMe cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, whereas apoptosis and cell-cycle blockade were investigated by high-content analysis. Bortezomib was also given to mice bearing i.p. xenografts of MMe cells, and its effects on tumor growth were evaluated.


RESULTS
Here, we show that NF-kappaB activity is a constitutive survival factor in transformed HMC, MMe cells, and acts as a survival factor in HMC exposed to asbestos fibers. Bortezomib inhibits NF-kappaB activity in MMe cells and induces cell cycle blockade and apoptosis in vitro as well as tumor growth inhibition in vivo.


CONCLUSIONS
Inhibition of NF-kappaB constitutive activation in MMe cells by Bortezomib resulted in in vitro cytotoxicity along with apoptosis and in vivo tumor regression. Our results support the use of Bortezomib in the treatment of MMe and has led to a phase II clinical trial currently enrolling in Europe.
Sartore-Bianchi
Andrea
A
Institute of Internal Medicine and Medical Oncology, IRCCS Policlinico San Matteo University Hospital, 1-27100 Pavia [corrected] Italy.
Gasparri
Fabio
F
Galvani
Arturo
A
Nici
Linda
L
Darnowski
James W
JW
Barbone
Dario
D
Fennell
Dean A
DA
Gaudino
Giovanni
G
Porta
Camillo
C
Mutti
Luciano
L
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009570:Nitriles; D061988:Proteasome Inhibitors; D011719:Pyrazines; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib