title: The proteasome inhibitor bortezomib synergizes with gemcitabine to block the growth of human 253JB-V bladder tumors in vivo.
abstract: Bortezomib (PS-341, Velcade) is a dipeptidyl boronic acid inhibitor of the 20S proteasome that was developed as a therapeutic agent for cancer. Here, we investigated the effects of bortezomib on the growth of human 253JB-V bladder cancer cells. Although the drug did not stimulate significant increases in levels of apoptosis, it inhibited cell growth in a concentration-dependent fashion and augmented the growth inhibitory effects of gemcitabine in vitro. These effects were associated with accumulation of p53 and p21 and suppression of cyclin-dependent kinase 2 activity. Bortezomib also inhibited secretion of the proangiogenic factors matrix metalloproteinase-9, interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF). In vivo studies with 253JB-V tumors growing in nude mice demonstrated that bortezomib (1 mg/kg) did not inhibit tumor growth when it was delivered as a single agent, although it reduced tumor microvessel density and inhibited expression of VEGF and IL-8. However, combination therapy with bortezomib plus gemcitabine produced synergistic tumor growth inhibition associated with strong suppression of tumor cell proliferation. Together, our results demonstrate that bortezomib has significant antiproliferative activity in aggressive bladder cancer cells, which is best exploited within the context of combination chemotherapy.
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kamat
authors.forename: Takashi
authors.initials: T
authors.lastname: Karashima
authors.forename: Darren W
authors.initials: DW
authors.lastname: Davis
authors.forename: Laura
authors.initials: L
authors.lastname: Lashinger
authors.forename: Menashe
authors.initials: M
authors.lastname: Bar-Eli
authors.forename: Randall
authors.initials: R
authors.lastname: Millikan
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
authors.forename: Colin P N
authors.initials: CP
authors.lastname: Dinney
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D016923:Cell Death; D002455:Cell Division; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D003546:Cysteine Endopeptidases; D053938:DNA Fragmentation; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D001897:Boronic Acids; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016209:Interleukin-8; D009097:Multienzyme Complexes; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D000069286:Bortezomib; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D003546:Cysteine Endopeptidases; D020780:Matrix Metalloproteinase 9; D046988:Proteasome Endopeptidase Complex; D000093542:Gemcitabine