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Regulated cell death (RCD) in cancer: key pathways and targeted therapies
Fu Peng1, Minru Liao1, Rui Qin2
1West China School of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
Abstract:
Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.
Insights
Regulated cell death (RCD) pathways are crucial in cancer development and offer new therapeutic targets. Small molecules targeting these RCD subroutines show promise for improved cancer treatment strategies.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Regulated cell death (RCD), also known as programmed cell death (PCD), is a vital biological process distinct from accidental cell death (ACD).
- Aberrant RCD pathways are increasingly recognized as key drivers in tumorigenesis, presenting opportunities for novel cancer therapies.
- Targeting RCD subroutines with small-molecule compounds is an emerging and promising therapeutic strategy for various human cancers.
Purpose of the Study:
- To review key apoptotic and autophagy-dependent cell death signaling pathways in cancer.
- To summarize crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis, and lysosome-dependent cell death (LCD).
- To discuss the current landscape of small-molecule compounds targeting RCD subroutines for cancer treatment.
Main Methods:
- Literature review of RCD pathways and their roles in cancer.
- Analysis of signaling mechanisms for various RCD subroutines (apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, etc.).
- Survey of small-molecule compounds and therapeutic strategies targeting RCD in cancer.
Main Results:
- Detailed overview of major RCD pathways and their involvement in cancer initiation and progression.
- Identification of multiple RCD subroutines as critical targets for therapeutic intervention.
- Compilation of current small-molecule drugs, including single-target, dual/multiple-target compounds, and drug combinations, aimed at RCD modulation.
Conclusions:
- Targeting diverse RCD subroutines with small-molecule drugs represents a significant advancement in cancer therapy.
- Exploring novel therapeutic strategies, such as drug combinations and emerging approaches, can exploit cancer cell vulnerabilities.
- Further research into RCD-targeting small molecules holds substantial promise for future cancer treatment directions.
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