Specific effects of bortezomib against experimental malignant pleural effusion: a preclinical study.
BACKGROUND
We have previously shown that nuclear factor (NF)-kappaB activation of mouse Lewis lung carcinoma (LLC) specifically promotes the induction of malignant pleural effusions (MPE) by these cells. In the present studies we hypothesized that treatment of immunocompetent mice with bortezomib tailored to inhibit cancer cell NF-kappaB activation and not proliferation specifically inhibits MPE formation by LLC cells.


RESULTS
Treatment of LLC cells with low concentrations of bortezomib (100 ng/ml) inhibited NF-kappaB activation and NF-kappaB-dependent transcription, but not cellular proliferation. Bortezomib treatment of immunocompetent C57BL/6 mice bearing LLC-induced subcutaneous tumors and MPEs significantly blocked tumor-specific NF-kappaB activation. However, bortezomib treatment did not impair subcutaneous LLC tumor growth, but was effective in limiting LLC-induced MPE. This specific effect was evidenced by significant reductions in effusion accumulation and the associated mortality and was observed with both preventive (beginning before MPE formation) and therapeutic (beginning after MPE establishment) bortezomib treatment. The favorable impact of bortezomib on MPE was associated with suppression of cardinal MPE-associated phenomena, such as inflammation, vascular hyperpermeability, and angiogenesis. In this regard, therapeutic bortezomib treatment had identical favorable results on MPE compared with preventive treatment, indicating that the drug specifically counteracts effusion formation.


CONCLUSIONS
These studies indicate that proteasome inhibition tailored to block NF-kappaB activation of lung adenocarcinoma specifically targets the effusion-inducing phenotype of this tumor. Although the drug has limited activity against advanced solid lung cancer, it may prove beneficial for patients with MPE.
Psallidas
Ioannis
I
Applied Biomedical Research & Training Center "Marianthi Simou", Department of Critical Care & Pulmonary Services, General Hospital "Evangelismos", National and Kapodistrian University of Athens, Greece.
Karabela
Sophia P
SP
Moschos
Charalampos
C
Sherrill
Taylor P
TP
Kollintza
Androniki
A
Magkouta
Sophia
S
Theodoropoulou
Panagiota
P
Roussos
Charis
C
Blackwell
Timothy S
TS
Kalomenidis
Ioannis
I
Stathopoulos
Georgios T
GT
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007249:Inflammation / Q000150:complications / Q000188:drug therapy; D018836:Inflammation Mediators / Q000378:metabolism; D008175:Lung Neoplasms / Q000150:complications / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000150:complications / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000150:complications / Q000188:drug therapy; D016066:Pleural Effusion, Malignant / Q000150:complications / Q000188:drug therapy*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*
D001897:Boronic Acids; D018836:Inflammation Mediators; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex