A novel, soluble compound, C25, sensitizes to TRAIL-induced apoptosis through upregulation of DR5 expression. Anticancer Drugs 2015 Jun;26(5):518-30
Date
02/04/2015Pubmed ID
25646742DOI
10.1097/CAD.0000000000000213Scopus ID
2-s2.0-84939967936 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
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.
Author List
James MA, Seibel WL, Kupert E, Hu XX, Potharla VY, Anderson MWMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Apoptosis
Caspase 3
Cell Line, Tumor
Databases, Chemical
Drug Screening Assays, Antitumor
Drug Synergism
Female
Heterografts
Humans
Hydrazones
Mice, Nude
Mitochondria
Neoplasm Transplantation
Pyrazoles
Receptors, TNF-Related Apoptosis-Inducing Ligand
Signal Transduction
Solubility
TNF-Related Apoptosis-Inducing Ligand
Tumor Burden
Up-Regulation
