The efficacy of hyperthermia-based multimodal therapy is dependent on gatekeeper protein, BID
Objectives The combination of ferroptotic agent artesunate (ART) and apoptotic agent rhTRAIL (recombinant human tumor necrosis factor-related apoptosis-inducing ligand) has been shown to synergistically enhance apoptosis in various cancer cell lines via crosstalk between the endoplasmic reticulum (E...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2025-12-01
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| Series: | International Journal of Hyperthermia |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/02656736.2025.2544017 |
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| Summary: | Objectives The combination of ferroptotic agent artesunate (ART) and apoptotic agent rhTRAIL (recombinant human tumor necrosis factor-related apoptosis-inducing ligand) has been shown to synergistically enhance apoptosis in various cancer cell lines via crosstalk between the endoplasmic reticulum (ER) stress response, the rhTRAIL-induced extrinsic cell death receptor pathway, and the intrinsic BID-Bax-mitochondrial-dependent-apoptosis pathway. This synergistic interaction has been demonstrated to be effective in multiple types of cancer cell lines, making artesunate combined with rhTRAIL a promising second-line therapy for colon cancer patients after cytoreductive surgery and chemotherapeutic treatments. To further enhance the second-line therapy’s tumoricidal effect, a multimodal therapy was developed by combining artesunate, rhTRAIL, and hyperthermic conditions where samples were treated at 42 °C for 1 h.Methods The effects of this therapy were tested in human colon carcinoma HCT116 and pancreatic adenocarcinoma BxPC-3 cell models. The cytotoxic and synergistic effects were analyzed using fluorescence microscopy, cell survival assays, and protein analysis through Western blotting.Results Our findings demonstrated a significant enhancement of apoptosis when artesunate and rhTRAIL treatments were combined with heat exposure. The synergistic and apoptotic effect of the agents was effectively abrogated in BID-deficient and BID mutant-type cells as well as Bax-deficient cells, but not Bak-deficient cells.Conclusions The results suggest that BID acts as a key gatekeeper molecule of apoptosis during hyperthermia-based multimodal treatment. These findings raise important questions about the underlying mechanisms of heat-induced apoptosis and its involvement in orchestrating various cellular stress pathways. |
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| ISSN: | 0265-6736 1464-5157 |