TRAILblazing Strategies for Cancer Treatment
In the late 1990s, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF-family, started receiving much attention for its potential in cancer therapy, due to its capacity to induce apoptosis selectively in tumour cells in vivo. TRAIL binds to its membrane-bound d...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-03-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/11/4/456 |
| _version_ | 1797721797269913600 |
|---|---|
| author | Anna-Laura Kretz Anna Trauzold Andreas Hillenbrand Uwe Knippschild Doris Henne-Bruns Silvia von Karstedt Johannes Lemke |
| author_facet | Anna-Laura Kretz Anna Trauzold Andreas Hillenbrand Uwe Knippschild Doris Henne-Bruns Silvia von Karstedt Johannes Lemke |
| author_sort | Anna-Laura Kretz |
| collection | DOAJ |
| description | In the late 1990s, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF-family, started receiving much attention for its potential in cancer therapy, due to its capacity to induce apoptosis selectively in tumour cells in vivo. TRAIL binds to its membrane-bound death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) inducing the formation of a death-inducing signalling complex (DISC) thereby activating the apoptotic cascade. The ability of TRAIL to also induce apoptosis independently of p53 makes TRAIL a promising anticancer agent, especially in p53-mutated tumour entities. Thus, several so-called TRAIL receptor agonists (TRAs) were developed. Unfortunately, clinical testing of these TRAs did not reveal any significant anticancer activity, presumably due to inherent or acquired TRAIL resistance of most primary tumour cells. Since the potential power of TRAIL-based therapies still lies in TRAIL’s explicit cancer cell-selectivity, a desirable approach going forward for TRAIL-based cancer therapy is the identification of substances that sensitise tumour cells for TRAIL-induced apoptosis while sparing normal cells. Numerous of such TRAIL-sensitising strategies have been identified within the last decades. However, many of these approaches have not been verified in animal models, and therefore potential toxicity of these approaches has not been taken into consideration. Here, we critically summarise and discuss the status quo of TRAIL signalling in cancer cells and strategies to force tumour cells into undergoing apoptosis triggered by TRAIL as a cancer therapeutic approach. Moreover, we provide an overview and outlook on innovative and promising future TRAIL-based therapeutic strategies. |
| first_indexed | 2024-03-12T09:38:24Z |
| format | Article |
| id | doaj.art-afd422fac50f48da84e0416f28012e28 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T09:38:24Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-afd422fac50f48da84e0416f28012e282023-09-02T13:27:26ZengMDPI AGCancers2072-66942019-03-0111445610.3390/cancers11040456cancers11040456TRAILblazing Strategies for Cancer TreatmentAnna-Laura Kretz0Anna Trauzold1Andreas Hillenbrand2Uwe Knippschild3Doris Henne-Bruns4Silvia von Karstedt5Johannes Lemke6Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, GermanyInstitute for Experimental Cancer Research, University of Kiel, 24105 Kiel, GermanyDepartment of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, GermanyDepartment of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, GermanyDepartment of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, GermanyDepartment of Translational Genomics, University Hospital Cologne, Weyertal 115b, 50931 Cologne, GermanyDepartment of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, GermanyIn the late 1990s, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF-family, started receiving much attention for its potential in cancer therapy, due to its capacity to induce apoptosis selectively in tumour cells in vivo. TRAIL binds to its membrane-bound death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) inducing the formation of a death-inducing signalling complex (DISC) thereby activating the apoptotic cascade. The ability of TRAIL to also induce apoptosis independently of p53 makes TRAIL a promising anticancer agent, especially in p53-mutated tumour entities. Thus, several so-called TRAIL receptor agonists (TRAs) were developed. Unfortunately, clinical testing of these TRAs did not reveal any significant anticancer activity, presumably due to inherent or acquired TRAIL resistance of most primary tumour cells. Since the potential power of TRAIL-based therapies still lies in TRAIL’s explicit cancer cell-selectivity, a desirable approach going forward for TRAIL-based cancer therapy is the identification of substances that sensitise tumour cells for TRAIL-induced apoptosis while sparing normal cells. Numerous of such TRAIL-sensitising strategies have been identified within the last decades. However, many of these approaches have not been verified in animal models, and therefore potential toxicity of these approaches has not been taken into consideration. Here, we critically summarise and discuss the status quo of TRAIL signalling in cancer cells and strategies to force tumour cells into undergoing apoptosis triggered by TRAIL as a cancer therapeutic approach. Moreover, we provide an overview and outlook on innovative and promising future TRAIL-based therapeutic strategies.https://www.mdpi.com/2072-6694/11/4/456TRAIL signallingTRAIL sensitisingTRAIL-induced apoptosisTRAIL in cancer |
| spellingShingle | Anna-Laura Kretz Anna Trauzold Andreas Hillenbrand Uwe Knippschild Doris Henne-Bruns Silvia von Karstedt Johannes Lemke TRAILblazing Strategies for Cancer Treatment Cancers TRAIL signalling TRAIL sensitising TRAIL-induced apoptosis TRAIL in cancer |
| title | TRAILblazing Strategies for Cancer Treatment |
| title_full | TRAILblazing Strategies for Cancer Treatment |
| title_fullStr | TRAILblazing Strategies for Cancer Treatment |
| title_full_unstemmed | TRAILblazing Strategies for Cancer Treatment |
| title_short | TRAILblazing Strategies for Cancer Treatment |
| title_sort | trailblazing strategies for cancer treatment |
| topic | TRAIL signalling TRAIL sensitising TRAIL-induced apoptosis TRAIL in cancer |
| url | https://www.mdpi.com/2072-6694/11/4/456 |
| work_keys_str_mv | AT annalaurakretz trailblazingstrategiesforcancertreatment AT annatrauzold trailblazingstrategiesforcancertreatment AT andreashillenbrand trailblazingstrategiesforcancertreatment AT uweknippschild trailblazingstrategiesforcancertreatment AT dorishennebruns trailblazingstrategiesforcancertreatment AT silviavonkarstedt trailblazingstrategiesforcancertreatment AT johanneslemke trailblazingstrategiesforcancertreatment |