title: A Smac mimetic augments the response of urothelial cancer cells to gemcitabine and cisplatin.
abstract: Cisplatin-based chemotherapy is considered the gold standard for patients with advanced bladder cancer. However, despite initial response, many patients will relapse; therefore, novel salvage treatment strategies are desperately needed. Herein, we studied a mechanism based treatment combination using a Smac mimetic with standard chemotherapy. Using a panel of 10 urothelial cancer cell lines, we exposed them to a combination of gemcitabine, cisplatin, and a Smac mimetic. Sensitivity was determined using a DNA fragmentation assay. We determined that three cell lines (UMUC-3, UMUC-13, and RT4v6) were considered sensitive to the combination of gemcitabine and cisplatin and an additional three cell lines were sensitized to gemcitabine and cisplatin with the addition of the Smac mimetic (UMUC-6, UMUC-12, and UMUC-18). We next explored the constitutive expression of selected members of the IAP family (XIAP, cIAP-1, cIAP-2, and Survivin), the BCL family (BCL-2, BCLXL, and BAX) and Smac using gene expression profiling and western blotting. We determined that RNA and protein expression of SMAC, selected members of the IAP family and members of the BCL family did not correlate to drug sensitivity. Lastly, using an in vivo mouse model, we determined that treatment with the Smac mimetic in combination with gemcitabine and cisplatin resulted in increased apoptosis, decreased microvessel density and decreased cellular proliferation. This novel treatment strategy may be effective in patients with advanced urothelial carcinoma and warrants further investigation.
authors.affiliation: Department of Urology; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
authors.forename: Eugene K
authors.initials: EK
authors.lastname: Lee
authors.affiliation: Department of Urology; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
authors.forename: Goodwin
authors.initials: G
authors.lastname: Jinesh G
authors.affiliation: AstraZeneca R&D; Boston, MA USA.
authors.forename: Naomi M
authors.initials: NM
authors.lastname: Laing
authors.affiliation: Department of Urology; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
authors.forename: Woonyoung
authors.initials: W
authors.lastname: Choi
authors.affiliation: Department of Urology; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
authors.affiliation: Department of Urology; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kamat
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D019254:Genes, bcl-2; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018716:Molecular Mimicry; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology*; D019459:Urothelium / Q000473:pathology*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine
keywords: SMAC mimetic; bladder cancer; chemotherapy; cisplatin; gemcitabine