Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas.
Primary effusion lymphomas (PELs) are a rare type of non-Hodgkin's lymphoma that are resistant to cytotoxic chemotherapy. PELs manifest constitutive activation of nuclear factor kappa B (NF-kappaB), and inhibition of NF-kappaB induces apoptosis of PELs and sensitizes to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced death. Bortezomib (PS-341), a peptidyl boronic acid inhibitor of the proteasome, is a potent agent against a wide range of hematologic malignancies and has been shown to inhibit NF-kappaB. Thus, we examined the cytotoxic effects of bortezomib alone and in combination with various drugs. Bortezomib potently inhibited NF-kappaB in PEL cells in a dose-dependent manner. In addition, bortezomib inhibited growth and induced apoptosis of PEL cell lines (IC(50) values of 3.4-5.0 nM). Results of drug interactions between bortezomib and chemotherapy (doxorubicin and Taxol) were schedule-dependent: synergistic interactions were generally observed when PEL cells were pretreated with bortezomib prior to chemotherapy, whereas additive or even antagonistic interactions occurred with chemotherapy pretreatment or simultaneous treatment with bortezomib and chemotherapy. Most schedules of bortezomib and dexamethasone were synergistic, although pretreatment with dexamethasone resulted in additive interactions. Effects of combinations of bortezomib and TRAIL were generally additive. Thus, bortezomib represents a promising potential therapy for the treatment of PEL.
An
J
J
VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
Sun
Y
Y
Fisher
M
M
Rettig
M B
MB
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004347:Drug Interactions; D004357:Drug Synergism; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000008:administration & dosage; D016328:NF-kappa B / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage; D016066:Pleural Effusion, Malignant / Q000188:drug therapy* / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin; D017239:Paclitaxel