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Cancer therapy in the necroptosis era
1Department of Biochemistry and Molecular Biology, Medical School, Southeast University, Nanjing, Jiangsu 210009, China.
Abstract:
Necroptosis is a caspase-independent form of regulated cell death executed by the receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like protein (MLKL). Recently, necroptosis-based cancer therapy has been proposed to be a novel strategy for antitumor treatment. However, a big controversy exists on whether this type of therapy is feasible or just a conceptual model. Proponents believe that because necroptosis and apoptosis use distinct molecular pathways, triggering necroptosis could be an alternative way to eradicate apoptosis-resistant cancer cells. This hypothesis has been preliminarily validated by recent studies. However, some skeptics doubt this strategy because of the intrinsic or acquired defects of necroptotic machinery observed in many cancer cells. Moreover, two other concerns are whether or not necroptosis inducers are selective in killing cancer cells without disturbing the normal cells and whether it will lead to inflammatory diseases. In this review, we summarize current studies surrounding this controversy on necroptosis-based antitumor research and discuss the advantages, potential issues, and countermeasures of this novel therapy.
Insights
Necroptosis, a programmed cell death pathway involving RIP1, RIP3, and MLKL, shows promise for cancer therapy by targeting apoptosis-resistant cells. However, its clinical feasibility faces challenges due to cancer cell defects and potential side effects.
Area of Science:
- Biochemistry and Molecular Biology
- Oncology
- Immunology
Background:
- Necroptosis is a regulated cell death pathway mediated by RIP1, RIP3, and MLKL.
- Emerging research explores necroptosis as a novel cancer therapy strategy, particularly for apoptosis-resistant tumors.
Purpose of the Study:
- To review the current controversies and evidence surrounding necroptosis-based antitumor therapy.
- To discuss the potential advantages, challenges, and future directions for this therapeutic approach.
Main Methods:
- Literature review of recent studies on necroptosis and cancer.
- Analysis of the molecular mechanisms underlying necroptosis induction and regulation.
- Evaluation of the potential benefits and risks of necroptosis-based cancer treatments.
Main Results:
- Necroptosis offers an alternative to apoptosis, potentially overcoming cancer cell resistance.
- Challenges include defects in necroptotic machinery in cancer cells and potential off-target effects.
- Concerns exist regarding the selectivity of necroptosis inducers and the risk of inflammatory diseases.
Conclusions:
- Necroptosis-based cancer therapy is a promising but controversial strategy.
- Further research is needed to address the limitations and optimize the application of necroptosis inducers.
- Developing selective inducers and managing potential side effects are crucial for clinical translation.
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