Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target
Abstract
:1. Introduction
2. Necroptosis Induction
2.1. Pro-Survival Signalling Complex I
2.2. Cell Death-Inducing Signalling Complex II
Inhibition of Caspase-8 Activity Is Essential for Necroptosis
3. RIPK1 Has Multiple Functions
4. RIPK3 Plays a Key Role in Necroptosis
5. MLKL Is the Effector Protein in Necroptosis
6. The Necroptotic Pathway as Therapeutic Target
6.1. Necroptosis in Neurodegenerative Diseases
6.2. Necroptosis in Rheumatoid Arthritis
6.3. Necroptosis in Kidney Injury
6.4. Necroptosis in Circulatory System Diseases
6.5. Necroptosis in Diabetes
6.6. Necroptosis in Cancers
7. Conclusions
Funding
Conflicts of Interest
References
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Apoptosis | Necroptosis | Necrosis |
---|---|---|
Regulated | Regulated | Unregulated |
Triggered by specific cytokines | Triggered by specific cytokines | Induced by damaging environmental stress (such as extreme physiological stress and viral or toxin-mediated infections) |
Shrinkage of cell | Rapid swelling of cell | Cell swelling |
- | Swelling of organelles | Swelling of organelles |
Blebbing of plasma membrane | Disruption of plasma membrane | Loss of membrane integrity |
Formation of apoptotic bodies | Organelle breakdown | |
- | Release of cellular contents | Release of cellular contents |
- | Pro-inflammatory response | Pro-inflammatory response |
Compound Name | Target | References |
---|---|---|
Necrostatins (necrostatin-1, 7-Cl-O-necrostatin) | RIPK1 | [1,41] |
GSK2982772 | RIPK1 | [42] |
GSK3145095 | RIPK1 | (Clinicaltrials.gov) |
RIPA-56 | RIPK1 | [40] |
Ponatinib | RIPK1/RIPK3 | [43] |
Pazopanib | RIPK1 | [43] |
DNL747 | RIPK1 | (Clinicaltrials.gov) |
GSK’840, GSK’843 and GSK’872 | RIPK3 | [44,45] |
Dabrafenib | RIPK3 | [46] |
HS-1371 | RIPK3 | [47] |
GW806742X | MLKL | [48] |
Necrosulfonamide (NSA) | MLKL | [49] |
17AAG | HSP90 | [50] |
Compound Name | Target | Phase | Disease Condition | Identifier | Study Type | Status (Oct 2019) |
---|---|---|---|---|---|---|
GSK2982772 | RIPK1 | II | Ulcerative colitis | NCT02903966 | With placebo | Completed |
I | Rheumatoid arthritis | NCT02858492 | With placebo | Completed | ||
II | Psoriasis | NCT02776033 | With placebo | Completed | ||
GSK3145095 | I | Solid tumors | NCT03681951 | With Pembrolizumab | Terminated | |
Dabrafenib | RIPK3 | IV | Melanoma Non-small cell lung cancer Solid tumor Rare cancers High grade glioma | NCT03340506 | With trametinib | Recruiting |
II | Metastatic colorectal cancer | NCT03668431 | With trametinib and PDR001 | Recruiting | ||
II | Melanoma | NCT01682213 | Single agent | Completed | ||
II | BRAF Mutation-Positive Malignant Melanoma and Brain Metastases | NCT02974803 | With trametinib and stereotactic radiation | Active, not recruiting | ||
II | Metastatic Melanoma (Carrying BRAF V600 Mutation) | NCT02052193 | With vemurafenib | Terminated | ||
III | Malignant Melanoma | NCT03551626 | With trametinib | Recruiting | ||
Ponatinib | RIPK/RIPK3 | Chronic Myeloid Leukemia (CML) Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) | NCT01592136 | Expanded Access | Approved for marketing | |
II | Non-small cell lung cancer | NCT01813734 | Single agent | Completed | ||
II | Leukemia | NCT01570868 | Single agent | Terminated | ||
II/III | Non-small cell lung cancer head and neck Cancer | NCT01761747 | Single agent | Terminated | ||
I/II | Acute myeloid leukemia | NCT02428543 | With cytarabine | Recruiting | ||
II | Medullary thyroid cancer | NCT03838692 | Single agent | Not yet recruiting | ||
Pazopanib | RIPK1 | I | Renal cell carcinoma Soft tissue sarcoma Metastatic disease | NCT02795819 | With AR-42 | Terminated |
II | Renal Cell carcinoma | NCT01545817 | Pazopanib followed by everolimus | Terminated | ||
DNL747 | RIPK1 | I | AD | NCT03757325 | With Placebo | Recruiting |
I | ALS | NCT03757351 | With Placebo | Recruiting | ||
17AAG | HSP90 | II | Anaplastic Large Cell Lymphoma Recurrent Adult Hodgkin Lymphoma Recurrent Mantle Cell Lymphoma | NCT00117988 | Single agent | Completed |
I | Unspecified Adult Solid Tumor, Protocol Specific | NCT00121264 | With sorafenib tosylate | Completed | ||
I | Relapsed or Refractory Hematologic Cancer | NCT00103272 | With bortezomib | Terminated | ||
IPI-504 | HSP90 | I | Solid Tumors | NCT00606814 | With Docetaxel | Completed |
I | Multiple Myeloma | NCT00113204 | Single agent | Completed | ||
II | Prostate Cancer | NCT00564928 | Single agent | Completed |
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Chen, J.; Kos, R.; Garssen, J.; Redegeld, F. Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target. Cells 2019, 8, 1486. https://doi.org/10.3390/cells8121486
Chen J, Kos R, Garssen J, Redegeld F. Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target. Cells. 2019; 8(12):1486. https://doi.org/10.3390/cells8121486
Chicago/Turabian StyleChen, Jing, Renate Kos, Johan Garssen, and Frank Redegeld. 2019. "Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target" Cells 8, no. 12: 1486. https://doi.org/10.3390/cells8121486
APA StyleChen, J., Kos, R., Garssen, J., & Redegeld, F. (2019). Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target. Cells, 8(12), 1486. https://doi.org/10.3390/cells8121486