Combination therapy with IFN-alpha plus bortezomib induces apoptosis and inhibits angiogenesis in human bladder cancer cells.
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-alpha 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 interleukin-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-alpha 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-alpha plus bortezomib is effective but can work via different mechanisms (apoptosis versus angiogenesis inhibition) in preclinical models of human bladder cancer.
Papageorgiou
Angela
A
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Box 173, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Kamat
Ashish
A
Benedict
William F
WF
Dinney
Colin
C
McConkey
David J
DJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D048708:Cell Growth Processes / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D016209:Interleukin-8 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D011719:Pyrazines / Q000008:administration & dosage; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis; D001749:Urinary Bladder Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
D001897:Boronic Acids; D016898:Interferon-alpha; D016209:Interleukin-8; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000069286:Bortezomib