title: A novel, soluble compound, C25, sensitizes to TRAIL-induced apoptosis through upregulation of DR5 expression.
abstract: The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential therapeutic agent that induces apoptosis selectively in tumor cells. However, numerous solid tumor types are resistant to TRAIL. Sensitization to TRAIL has been an area of great research interest, but has met significant challenges because of poor bioavailability, half-life, and solubility of sensitizing compounds such as curcumin. Soluble, TRAIL-sensitizing compounds were screened on the basis of similarity to the redox-active substructure of curcumin and sensitization to TRAIL-induced apoptosis. We determined the effect of the lead compound, C25, in combination with TRAIL in human cancer cell lines using MTS proliferation assays, apoptosis assays, and western blotting. Short hairpin RNA knockdown of death receptor 5 (DR5) was performed to determine whether DR5 upregulation was required for TRAIL-mediated apoptosis. In-vivo efficacy was determined using human lung tumor xenograft models. C25 helped overcome TRAIL resistance by upregulating the expression of the TRAIL receptor DR5 and apoptosis in several tumor cell lines. Blockade of DR5 expression abrogated C25 sensitization to TRAIL, demonstrating the requirement for DR5 upregulation for C25-mediated potentiation of TRAIL-mediated apoptosis. The combination of C25 and TRAIL effectively inhibited tumorigenesis in vivo. This study demonstrates the synergistic efficacy of C25 in sensitization to TRAIL-induced apoptosis in multiple tumor cell types, including highly resistant lung and ovarian tumor cell lines. Furthermore, C25 was efficacious against tumor growth in vivo. Thus, C25 may be a potential therapeutic for cancer in combination with TRAIL or DR5 agonist therapy.
authors: Departments of aSurgery bMedicine, MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin cDrug Discovery Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors: Michael A
authors: MA
authors: James
authors: William L
authors: WL
authors: Seibel
authors: Elena
authors: E
authors: Kupert
authors: Xiao X
authors: XX
authors: Hu
authors: Vishwakanth Y
authors: VY
authors: Potharla
authors: Marshall W
authors: MW
authors: Anderson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D062126:Databases, Chemical; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D064593:Heterografts; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009368:Neoplasm Transplantation; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction; D012995:Solubility; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; D011720:Pyrazoles; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D053148:Caspase 3