title: A humanized leucine zipper-TRAIL hybrid induces apoptosis of tumors both in vitro and in vivo.
abstract: Evidence suggests that stimulating apoptosis in malignant cells without inflicting collateral damage to the host's normal tissues is a promising cancer therapy. Chemo- and radiation therapies that, especially if combined, induce apoptosis in tumor cells have been used for treating cancer patients for decades. These treatments, however, are limited in their ability to discriminate between malignant and non-malignant cells and, therefore, produce substantial healthy tissue damage and subsequent toxic side-effects. In addition, as a result of these therapies, many tumor types acquire an apoptosis-resistant phenotype and become more aggressive and metastatic. Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) has been considered a promising and reliable selective inducer of apoptosis in cancerous cells. TRAIL, however, is not uniformly effective in cancer and multiple cancer cell types are considered resistant to natural TRAIL. To overcome this deficiency of TRAIL, we have earlier constructed a yeast-human hybrid leucine zipper-TRAIL in which the yeast GCN4-pII leucine zipper was fused to human TRAIL (GCN4-TRAIL). This construct exhibited a significantly improved anti-tumor apoptotic activity and safety, but is potentially immunogenic in humans. Here, we report a novel, potent, and fully human ATF7 leucine zipper-TRAIL (ATF7-TRAIL) fusion construct that is expected to have substantially lower immunogenicity. In solution, ATF7-TRAIL exists solely as a trimer with a Tm of 80°C and is active against cancer cells both in vitro and in vivo, in a mouse tumor xenograft model. Our data suggest that our re-engineered TRAIL is a promising candidate for further evaluation as an antitumor agent.
authors: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, United States of America.
authors: Dmitri
authors: D
authors: Rozanov
authors: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, United States of America.
authors: Paul
authors: P
authors: Spellman
authors: Sanford Research, Sioux Falls, South Dakota, United States of America.
authors: Alexei
authors: A
authors: Savinov
authors: Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors: Alex Y
authors: AY
authors: Strongin
mesh_terms: D051696:Activating Transcription Factors / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C427752:ATF7 protein, human; D051696:Activating Transcription Factors; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand