Targeting Regulated Cell Death Pathways in Cancers for Effective Treatment: a Comprehensive Review

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2024 Dec 2

PMID 39620145

Authors

Ruchi Saxena

Craig M Welsh

You-Wen He

Affiliations

Soon will be listed here.

Abstract

Cancer is a complex disease characterized by specific "mission-critical" events that drive the uncontrolled growth and spread of tumor cells and their offspring. These events are essential for the advancement of the disease. One of the main contributors to these events is dysregulation of cell death pathways-such as apoptosis, necroptosis, ferroptosis, autophagy, pyroptosis, cuproptosis, parthanatos and-allows cancer cells to avoid programmed cell death and continue proliferating unabated. The different cell death pathways in cancers provide useful targets for cancer treatment. This review examines recent progresses in the preclinical and clinical development of targeting dysregulated cell death pathways for cancer treatment. To develop effective cancer therapies, it is essential to identify and target these mission-critical events that prevent tumor cells from timely death. By precisely targeting these crucial events, researchers can develop therapies with maximum impact and minimal side effects. A comprehensive understanding of the molecular and cellular mechanisms underlying these regulated cell death pathways will further the development of highly effective and personalized cancer treatments.

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References

Liu X, Zhou M, Mei L, Ruan J, Hu Q, Peng J . Key roles of necroptotic factors in promoting tumor growth. Oncotarget. 2016; 7(16):22219-33. PMC: 5008357. DOI: 10.18632/oncotarget.7924. View

Cao L, Mu W . Necrostatin-1 and necroptosis inhibition: Pathophysiology and therapeutic implications. Pharmacol Res. 2020; 163:105297. PMC: 7962892. DOI: 10.1016/j.phrs.2020.105297. View

Ye L, Chaudhary K, Zandkarimi F, Harken A, Kinslow C, Upadhyayula P . Radiation-Induced Lipid Peroxidation Triggers Ferroptosis and Synergizes with Ferroptosis Inducers. ACS Chem Biol. 2020; 15(2):469-484. PMC: 7180072. DOI: 10.1021/acschembio.9b00939. View

Yoshii J, Yoshiji H, Kuriyama S, Ikenaka Y, Noguchi R, Okuda H . The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells. Int J Cancer. 2001; 94(6):768-73. DOI: 10.1002/ijc.1537. View

Andreeff M, Kelly K, Yee K, Assouline S, Strair R, Popplewell L . Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia. Clin Cancer Res. 2015; 22(4):868-76. PMC: 4809642. DOI: 10.1158/1078-0432.CCR-15-0481. View

Fenton S, Hussain M . Olaparib monotherapy or in combination with abiraterone for treating mutated metastatic castration-resistant prostate cancer: alone or stronger together?. Expert Opin Investig Drugs. 2024; 33(10):993-999. DOI: 10.1080/13543784.2024.2391828. View

Debnath J, Gammoh N, Ryan K . Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. 2023; 24(8):560-575. PMC: 9980873. DOI: 10.1038/s41580-023-00585-z. View

Park J, Huang S, Wu T, Foster N, Sinicrope F . Prognostic impact of Beclin 1, p62/sequestosome 1 and LC3 protein expression in colon carcinomas from patients receiving 5-fluorouracil as adjuvant chemotherapy. Cancer Biol Ther. 2012; 14(2):100-7. PMC: 3571991. DOI: 10.4161/cbt.22954. View

Rosenfeld M, Ye X, Supko J, Desideri S, Grossman S, Brem S . A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy. 2014; 10(8):1359-68. PMC: 4203513. DOI: 10.4161/auto.28984. View

10.

Li L, Peng X, Yang Z, Han N, Gou C, Shi J . Dihydroartemisinin-driven selective anti-lung cancer proliferation by binding to EGFR and inhibition of NRAS signaling pathway-induced DNA damage. Sci Rep. 2024; 14(1):11704. PMC: 11111767. DOI: 10.1038/s41598-024-62126-8. View

11.

Reed J . Drug insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nat Clin Pract Oncol. 2006; 3(7):388-98. DOI: 10.1038/ncponc0538. View

12.

Yan H, Luo B, Wu X, Guan F, Yu X, Zhao L . Cisplatin Induces Pyroptosis via Activation of MEG3/NLRP3/caspase-1/GSDMD Pathway in Triple-Negative Breast Cancer. Int J Biol Sci. 2021; 17(10):2606-2621. PMC: 8315016. DOI: 10.7150/ijbs.60292. View

13.

Wang X, Chen Y, Wang X, Tian H, Wang Y, Jin J . Stem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11. Cancer Res. 2021; 81(20):5217-5229. PMC: 8530936. DOI: 10.1158/0008-5472.CAN-21-0567. View

14.

Wang H, Sun L, Su L, Rizo J, Liu L, Wang L . Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell. 2014; 54(1):133-146. DOI: 10.1016/j.molcel.2014.03.003. View

15.

Ozyerli-Goknar E, Bagci-Onder T . Epigenetic Deregulation of Apoptosis in Cancers. Cancers (Basel). 2021; 13(13). PMC: 8267644. DOI: 10.3390/cancers13133210. View

16.

Dubuisson A, Micheau O . Antibodies and Derivatives Targeting DR4 and DR5 for Cancer Therapy. Antibodies (Basel). 2019; 6(4). PMC: 6698863. DOI: 10.3390/antib6040016. View

17.

Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J . Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359(4):378-90. DOI: 10.1056/NEJMoa0708857. View

18.

Zhang X, Walke G, Horvath I, Kumar R, Blockhuys S, Holgersson S . Memo1 binds reduced copper ions, interacts with copper chaperone Atox1, and protects against copper-mediated redox activity in vitro. Proc Natl Acad Sci U S A. 2022; 119(37):e2206905119. PMC: 9477392. DOI: 10.1073/pnas.2206905119. View

19.

Johnson D, Taabazuing C, Okondo M, Chui A, Rao S, Brown F . DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. Nat Med. 2018; 24(8):1151-1156. PMC: 6082709. DOI: 10.1038/s41591-018-0082-y. View

20.

Draganov D, Gopalakrishna-Pillai S, Chen Y, Zuckerman N, Moeller S, Wang C . Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. Sci Rep. 2015; 5:16222. PMC: 4639773. DOI: 10.1038/srep16222. View