title: Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma.
abstract: Renal cell carcinoma (RCC) is resistant to traditional cancer therapies, and metastatic RCC (mRCC) is incurable. The shortcomings in current therapeutic options for patients with mRCC provide the rationale for the development of novel treatment protocols. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has proven to be a potent inducer of tumor cell death in vitro and in vivo, and a number of TRAIL death receptor agonists (recombinant TRAIL or TRAIL death receptor-specific mAb) have been developed and tested clinically. Unfortunately the clinical efficacy of TRAIL has been underwhelming and is likely due to a number of possible mechanisms that render tumors resistant to TRAIL, prompting the search for drugs that increase tumor cell susceptibility to TRAIL. The objective of this study was to determine the effectiveness of combining the diterpene triepoxide triptolide, or its water-soluble prodrug, Minnelide, with TRAIL receptor agonists against RCC in vitro or in vivo, respectively. TRAIL-induced apoptotic death of human RCC cells was increased in the presence of triptolide. The triptolide-induced sensitization was accompanied by increased TRAIL-R2 (DR5) and decreased heat shock protein 70 expression. In vivo treatment of mice bearing orthotopic RCC (Renca) tumors showed the combination of Minnelide and agonistic anti-DR5 mAb significantly decreased tumor burden and increased animal survival compared to either therapy alone. Our data suggest triptolide/Minnelide sensitizes RCC cells to TRAIL-induced apoptosis through altered TRAIL death receptor and heat shock protein expression.
authors.affiliation: Department of Urology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Erik L
authors.initials: EL
authors.lastname: Brincks
authors.affiliation: Department of Urology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Kucaba
authors.affiliation: Department of Urology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Britnie R
authors.initials: BR
authors.lastname: James
authors.affiliation: Department of Urology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Murphy
authors.affiliation: Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455.|Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN 55455.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Schwertfeger
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Veena
authors.initials: V
authors.lastname: Sangwan
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Sulagna
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455.|Department of Surgery, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Saluja
authors.affiliation: Department of Urology, University of Minnesota, Minneapolis, MN 55455.|Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN 55455.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455.|Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Griffith
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D004852:Epoxy Compounds / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010755:Organophosphates / Q000494:pharmacology / Q000627:therapeutic use; D010616:Phenanthrenes / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D016019:Survival Analysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D004852:Epoxy Compounds; D010755:Organophosphates; D010616:Phenanthrenes; D011355:Prodrugs; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505640:Tnfrsf10b protein, mouse; C001899:triptolide; C579022:14-O-phosphonooxymethyltriptolide disodium salt
keywords: TRAIL; apoptosis; death receptor; renal cell carcinoma; triptolide