Drug interactions between the proteasome inhibitor bortezomib and cytotoxic chemotherapy, tumor necrosis factor (TNF) alpha, and TNF-related apoptosis-inducing ligand in prostate cancer.
OBJECTIVE
Proteasome inhibition has been shown to be an effective anticancer therapy in many tumor models, including prostate cancer. We sought to identify drug interactions between the proteasome inhibitor bortezomib and other apoptotic stimuli, including cytotoxic chemotherapy and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In addition, we wanted to gain insight into the role of nuclear factor kappaB inhibition as a mediator of bortezomib cytotoxic effects.


METHODS
Prostate cancer cell lines (LNCaP, LAPC4, CL1, and DU145) were treated with bortezomib and apoptotic stimuli (TRAIL, chemotherapy, and tumor necrosis factor alpha), alone or in combination. Apoptosis and cell viability were measured, and median effect/combination index analyses were used to quantitate drug interactions. Nuclear factor kappaB activity at baseline and in response to drug treatment was determined by gel shift and reporter gene assays.


RESULTS
Bortezomib induced cell death of androgen-dependent (LNCaP and LAPC4) and androgen-independent (CL1 and DU145) prostate cancer cell lines, although androgen-dependent cells were more sensitive to proteasome inhibition. Bortezomib synergized with TRAIL and tumor necrosis factor alpha to induce death in both androgen-dependent and androgen-independent cells.


CONCLUSIONS
Bortezomib and TRAIL represent a synergistic drug combination that warrants further evaluation in in vivo models of prostate cancer.
An
Jiabin
J
Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA.
Sun
Yi-Ping
YP
Adams
Julian
J
Fisher
Myrna
M
Belldegrun
Arie
A
Rettig
Matthew B
MB
D000728:Androgens / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000627:therapeutic use*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011480:Protease Inhibitors / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000627:therapeutic use*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D000728:Androgens; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001897:Boronic Acids; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; D008156:Luciferases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex