The proteasome inhibitor bortezomib augments anti-proliferative effects of mistletoe lectin-I and the PPAR-gamma agonist rosiglitazone in human melanoma cells.
BACKGROUND
The NFkappaB signalling pathway plays an important role in chemoresistance and decreased apoptosis. One indirect way to inhibit the NFkappaB pathway is to slow down the proteasomal degradation of its inhibitor IkappaB, thus preventing NFkappaB from translocation into the nucleus. Hence, the effect of the proteasome inhibitor bortezomib (Velcade) on the cell proliferation of the MV3, FemX-1 and G361 human melanoma cell lines and its action in combination with the PPAR-gamma agonist rosiglitazone or the mistletoe lectin ML-I, both having anti-proliferative effects on melanoma cells in single agent use, was investigated.


METHODS
Proliferation of melanoma cells under the different treatment regimes over a broad concentration range (0.0001-100 microg/ml) was assessed by means of the XTT cell proliferation assay.


RESULTS
At a concentration of 0.1 microg/ml bortezomib significantly reduced the proliferation rate of all melanoma cells to 1-13% of the control, which was mediated through increased apoptosis and inhibition of NFkappaB expression. Furthermore, the combination of bortezomib and rosiglitazone was the most potent and increased the effectiveness against melanoma cell growth by 63-71% (compared to single use of rosiglitazone) and by 27-39% (compared to single use of bortezomib), respectively.


CONCLUSIONS
This combination strategy might be a promising approach for future melanoma therapy.
Freudlsperger
Christian
C
Institut für Anatomie II: Experimentelle Morphologie, Universitätsklinikum Hamburg-Eppendorf 20246 Hamburg, Germany. c.freudlsperger@uke.uni-hamburg.de
Thies
Anka
A
Pfüller
Uwe
U
Schumacher
Udo
U
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists; D028321:Plant Preparations / Q000008:administration & dosage / Q000494:pharmacology*; D010940:Plant Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D054790:Ribosome Inactivating Proteins, Type 2; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D014118:Toxins, Biological / Q000008:administration & dosage / Q000494:pharmacology*
D001897:Boronic Acids; D047495:PPAR gamma; D028321:Plant Preparations; D010940:Plant Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D054790:Ribosome Inactivating Proteins, Type 2; D045162:Thiazolidinediones; D014118:Toxins, Biological; C488862:mistletoe lectin I; D000077154:Rosiglitazone; D000069286:Bortezomib