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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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | International Journal of Hyperthermia |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/02656736.2025.2544017 |
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| author | Sarah Helmueller Xinxin Song Dong-Hyun Kim Yong J. Lee |
| author_facet | Sarah Helmueller Xinxin Song Dong-Hyun Kim Yong J. Lee |
| author_sort | Sarah Helmueller |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e27f0bbdf5a94132a6b65528431eb059 |
| institution | Kabale University |
| issn | 0265-6736 1464-5157 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | International Journal of Hyperthermia |
| spelling | doaj-art-e27f0bbdf5a94132a6b65528431eb0592025-08-20T03:36:54ZengTaylor & Francis GroupInternational Journal of Hyperthermia0265-67361464-51572025-12-0142110.1080/02656736.2025.2544017The efficacy of hyperthermia-based multimodal therapy is dependent on gatekeeper protein, BIDSarah Helmueller0Xinxin Song1Dong-Hyun Kim2Yong J. Lee3Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USADepartment of Surgery, UT Southwestern Medical Center, Dallas, TX, USADepartment of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USADepartment of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USAObjectives 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.https://www.tandfonline.com/doi/10.1080/02656736.2025.2544017FerroptosisapoptosiscrosstalkBIDbakbax |
| spellingShingle | Sarah Helmueller Xinxin Song Dong-Hyun Kim Yong J. Lee The efficacy of hyperthermia-based multimodal therapy is dependent on gatekeeper protein, BID International Journal of Hyperthermia Ferroptosis apoptosis crosstalk BID bak bax |
| title | The efficacy of hyperthermia-based multimodal therapy is dependent on gatekeeper protein, BID |
| title_full | The efficacy of hyperthermia-based multimodal therapy is dependent on gatekeeper protein, BID |
| title_fullStr | The efficacy of hyperthermia-based multimodal therapy is dependent on gatekeeper protein, BID |
| title_full_unstemmed | The efficacy of hyperthermia-based multimodal therapy is dependent on gatekeeper protein, BID |
| title_short | The efficacy of hyperthermia-based multimodal therapy is dependent on gatekeeper protein, BID |
| title_sort | efficacy of hyperthermia based multimodal therapy is dependent on gatekeeper protein bid |
| topic | Ferroptosis apoptosis crosstalk BID bak bax |
| url | https://www.tandfonline.com/doi/10.1080/02656736.2025.2544017 |
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