Comparative Assessment of Various Formats of TRAIL in Three-Dimensional Cell Culture and Patient-Derived Tumoroids of Colorectal Cancer
Year: 2025
Type: article
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.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: Application of in vivo humanized PDX mouse model and ex vivo organoid model to assess the therapeutic efficacy of combinatorial therapy for pseudomyxoma peritonei, G344966962, G4119534169, G4682382839, G5370247717, G5850682332, ASSESSING THE PRECLINICAL EFFICACY OF COMBINED FERROPTOTIC AGENT AND SECRETORY TRAIL-ARMED NK CELLS FOR PSEUDOMYXOMA PERITONEI, G7639423629, G9000021776
OpenAlex ID: W4414375989
FWCI:
Cites:
Cited by:
Related to: