TY - JOUR
T1 - Combination therapy with IFN-α plus bortezomib induces apoptosis and inhibits angiogenesis in human bladder cancer cells
AU - Papageorgiou, Angela
AU - Kamat, Ashish
AU - Benedict, William F.
AU - Dinney, Colin
AU - McConkey, David J.
PY - 2006/12
Y1 - 2006/12
N2 - In a recent study, we showed that the proteasome inhibitor bortezomib sensitizes human bladder cancer cells to IFN-induced cell death. Here, we characterized the molecular mechanisms underlying the antitumoral effects of the combination in more detail. Bortezomib synergized with IFN-α to promote apoptosis via a tumor necrosis factor-related apoptosis-inducing ligand -associated mechanism but did not inhibit production of proangiogenic factors (vascular endothelial growth factor, basic fibroblast growth factor, and interieukin-8) in human UM-UC-5 cells. In contrast, exposure to the combination did not increase the levels of apoptosis in human UM-UC-3 cells but did inhibit the production of basic fibroblast growth factor and vascular endothelial growth factor. Studies with tumor xenografts confirmed that combination therapy with bortezomib plus IFN-α was effective in both models but that the effects were associated with differential effects on tumor necrosis factor-related apoptosis-inducing ligand -associated apoptosis (predominant in UM-UC-5) versus inhibition of angiogenesis (predominant in UM-UC-3). Together, our results show that combination therapy with IFN-α plus bortezomib is effective but can work via different mechanisms (apoptosis versus angiogenesis inhibition) in preclinical models of human bladder cancer.
AB - In a recent study, we showed that the proteasome inhibitor bortezomib sensitizes human bladder cancer cells to IFN-induced cell death. Here, we characterized the molecular mechanisms underlying the antitumoral effects of the combination in more detail. Bortezomib synergized with IFN-α to promote apoptosis via a tumor necrosis factor-related apoptosis-inducing ligand -associated mechanism but did not inhibit production of proangiogenic factors (vascular endothelial growth factor, basic fibroblast growth factor, and interieukin-8) in human UM-UC-5 cells. In contrast, exposure to the combination did not increase the levels of apoptosis in human UM-UC-3 cells but did inhibit the production of basic fibroblast growth factor and vascular endothelial growth factor. Studies with tumor xenografts confirmed that combination therapy with bortezomib plus IFN-α was effective in both models but that the effects were associated with differential effects on tumor necrosis factor-related apoptosis-inducing ligand -associated apoptosis (predominant in UM-UC-5) versus inhibition of angiogenesis (predominant in UM-UC-3). Together, our results show that combination therapy with IFN-α plus bortezomib is effective but can work via different mechanisms (apoptosis versus angiogenesis inhibition) in preclinical models of human bladder cancer.
UR - http://www.scopus.com/inward/record.url?scp=33846208703&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33846208703&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-05-0474
DO - 10.1158/1535-7163.MCT-05-0474
M3 - Article
C2 - 17172406
AN - SCOPUS:33846208703
SN - 1535-7163
VL - 5
SP - 3032
EP - 3041
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 12
ER -