{"doi":"10.29011/2574-710x.10302","title":"Comparative Assessment of Various Formats of TRAIL in Three-Dimensional Cell Culture and Patient-Derived Tumoroids of Colorectal Cancer","abstract":"Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising cytokine that selectively targets cancer cells while sparing normal tissues. Despite its favorable safety profile, clinical trials have demonstrated antitumor responses in only a small subset of patients. This limited efficacy has been largely attributed to the short plasma half-life of recombinant monomeric soluble TRAIL (rhTRAIL). To enhance its stability and therapeutic potential, researchers have developed modified versions, including an immunoglobulin Fc domain-fused TRAIL (Fc-TRAIL) and a dimeric Fc-fused single-chain variant (Fc-scTRAIL). In this study, we used the SNU-1746 three-dimensional (3D) multicellular layer culture model and a patient-derived colon cancer tumoroid model to evaluate the biological activity of these TRAIL formats (rhTRAIL, Fc-TRAIL, and Fc-scTRAIL). Treatment with rhTRAIL revealed that a longer exposure time (18-24 hours) was required to induce apoptosis in both 3D models, in contrast to monolayer cultures. Among the TRAIL formats, Fc-scTRAIL was the most potent in inducing apoptosis, as confirmed by immunoblotting analyses. Furthermore, artesunate (ART) enhanced TRAIL-induced apoptosis across all TRAIL formats, with the strongest synergistic effect observed in combination with Fc-scTRAIL. JC-1 staining assays indicated that mitochondrial membrane depolarization (a hallmark of the intrinsic apoptosis pathway) plays a key role in the cell death observed with the combination treatment in tumoroids. These findings provide compelling preclinical evidence supporting the potential of ART and Fc-scTRAIL combination therapy for future clinical evaluation.","journal":"Journal of Oncology Research and Therapy","year":2025,"id":575380,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9469,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1417499,"name":"Sarah Helmueller","orcid":null,"position":1,"is_corresponding":false},{"id":520891,"name":"Alexandra Gangi","orcid":"0000-0002-9512-7973","position":2,"is_corresponding":false},{"id":1483519,"name":"Ja-Lok Ku","orcid":null,"position":3,"is_corresponding":false},{"id":1263152,"name":"Roland E. Kontermann","orcid":"0000-0001-7139-1350","position":4,"is_corresponding":false},{"id":275455,"name":"Yong J. Lee","orcid":"0000-0001-5914-8489","position":5,"is_corresponding":false},{"id":1415558,"name":"Farzaneh Vafaeinik","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:57:48.486077Z","pmid":"41036530","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}