Manipulating Cell Death in Cancer

Ismail Ibrahim Al-Janabi

doi:10.54133/ajms.v9i1.2131

Authors

Ismail Ibrahim Al-Janabi Retired Academic, Freelance Consultant Pharmacist and Science Writer, Epsom, Surrey, UK https://orcid.org/0000-0003-2922-1790

DOI:

https://doi.org/10.54133/ajms.v9i1.2131

Keywords:

Apoptosis, Autophagy, Cell death pathways, Cancer therapy, Necroptosis

Abstract

Cancer cells often evade regulated cell death to maintain uncontrolled proliferation and withstand therapy. Targeting cell death pathways has emerged as a promising tactic for enhancing anticancer outcomes and overcoming treatment resistance. In addition to highlighting recent developments in therapeutic interventions, this review investigates the molecular mechanisms underlying the various forms of regulated cell deaths in cancer. We discuss small molecule inhibitors and immune-based approaches that take advantage of cell death pathways. Additionally, we address difficulties in clinical translation, such as tumor heterogeneity and off-target effects. This work offers insights into precision therapies that aim to manipulate cell death for better cancer treatment by clarifying the interplay between oncogenic signaling and cell death susceptibility.

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References

Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G. The molecular machinery of regulated cell death. Cell Res. 2019;29(5):347-364. doi: 10.1038/s41422-019-0164-5. DOI: https://doi.org/10.1038/s41422-019-0164-5

Lamichhane PP, Samir P. Cellular stress: Modulator of regulated cell death. Biology (Basel). 2023;12(9):1172. doi: 10.3390/biology12091172. DOI: https://doi.org/10.3390/biology12091172

Newton K, Strasser A, Kayagaki N, Dixit VM. Cell death. Cell. 2024;187(2):235-256. doi: 10.1016/j.cell.2023.11.044. DOI: https://doi.org/10.1016/j.cell.2023.11.044

Zhu Y, Yang R, Law JH, Khan M, Yip KW, Sun Q. Editorial: Hallmark of cancer: Resisting cell death. Front Oncol. 2022;12:1069947. doi: 10.3389/fonc.2022.1069947. DOI: https://doi.org/10.3389/fonc.2022.1069947

Li K, van Delft MF, Dewson G. Too much death can kill you: inhibiting intrinsic apoptosis to treat disease. EMBO J. 2021;40(14):e107341. doi: 10.15252/embj.2020107341. DOI: https://doi.org/10.15252/embj.2020107341

Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25(3):486-541. doi: 10.1038/s41418-017-0012-4. DOI: https://doi.org/10.1038/s41418-018-0102-y

Koren E, Fuchs Y. Modes of regulated cell death in cancer. Cancer Discov. 2021;11(2):245-265. doi: 10.1158/2159-8290.CD-20-0789. DOI: https://doi.org/10.1158/2159-8290.CD-20-0789

Gong L, Huang D, Shi Y, Liang Z, Bu H. Regulated cell death in cancer: from pathogenesis to treatment. Chin Med J (Engl). 2023;136(6):653-665. doi: 10.1097/CM9.0000000000002239. DOI: https://doi.org/10.1097/CM9.0000000000002239

Kayagaki N, Webster JD, Newton K. Control of cell death in health and disease. Annu Rev Pathol. 2024;19:157-180. doi: 10.1146/annurev-pathmechdis-051022-014433. DOI: https://doi.org/10.1146/annurev-pathmechdis-051022-014433

Saxena R, Welsh CM, He YW. Targeting regulated cell death pathways in cancers for effective treatment: a comprehensive review. Front Cell Dev Biol. 2024;12:1462339. doi: 10.3389/fcell.2024.1462339. DOI: https://doi.org/10.3389/fcell.2024.1462339

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70. doi: 10.1016/s0092-8674(00)81683-9. DOI: https://doi.org/10.1016/S0092-8674(00)81683-9

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013. PMID: 21376230. DOI: https://doi.org/10.1016/j.cell.2011.02.013

Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020;17(7):395-417. doi: 10.1038/s41571-020-0341-y. DOI: https://doi.org/10.1038/s41571-020-0341-y

Brumatti G, Salmanidis M, Ekert PG. Crossing paths: interactions between the cell death machinery and growth factor survival signals. Cell Mol Life Sci. 2010;67(10):1619-1630. doi: 10.1007/s00018-010-0288-8. DOI: https://doi.org/10.1007/s00018-010-0288-8

Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell. 2011;147(7):1640. PMID: 22078876. DOI: https://doi.org/10.1016/j.cell.2011.11.045

Roos WP, Thomas AD, Kaina B. DNA damage and the balance between survival and death in cancer biology. Nat Rev Cancer. 2016;16(1):20-33. doi: 10.1038/nrc.2015.2. DOI: https://doi.org/10.1038/nrc.2015.2

Galluzzi L, Kepp O, Kroemer G. Mitochondrial regulation of cell death: a phylogenetically conserved control. Microb Cell. 2016;3(3):101-108. doi: 10.15698/mic2016.03.483. DOI: https://doi.org/10.15698/mic2016.03.483

Lee E, Song CH, Bae SJ, Ha KT, Karki R. Regulated cell death pathways and their roles in homeostasis, infection, inflammation, and tumorigenesis. Exp Mol Med. 2023;55(8):1632-1643. doi: 10.1038/s12276-023-01069-y. DOI: https://doi.org/10.1038/s12276-023-01069-y

Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol. 2019;20(3):175-193. doi: 10.1038/s41580-018-0089-8. DOI: https://doi.org/10.1038/s41580-018-0089-8

Simpson CD, Mawji IA, Anyiwe K, Williams MA, Wang X, Venugopal AL, et al. Inhibition of the sodium potassium adenosine triphosphatase pump sensitizes cancer cells to anoikis and prevents distant tumor formation. Cancer Res. 2009;69(7):2739-2747. doi: 10.1158/0008-5472.CAN-08-2530. DOI: https://doi.org/10.1158/0008-5472.CAN-08-2530

Buchheit CL, Angarola BL, Steiner A, Weigel KJ, Schafer ZT. Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration. Cell Death Differ. 2015;22(8):1275-1286. doi: 10.1038/cdd.2014.209. DOI: https://doi.org/10.1038/cdd.2014.209

Wajant H. The Fas signaling pathway: more than a paradigm. Science. 2002;296(5573):1635-1636. doi: 10.1126/science.1071553. DOI: https://doi.org/10.1126/science.1071553

Mehlen P, Bredesen DE. Dependence receptors: from basic research to drug development. Sci Signal. 2011;4(157):mr2. doi: 10.1126/scisignal.2001521. DOI: https://doi.org/10.1126/scisignal.2001521

Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol. 2002;2(10):735-747. doi: 10.1038/nri911. DOI: https://doi.org/10.1038/nri911

Green DR, Oguin TH, Martinez J. The clearance of dying cells: table for two. Cell Death Differ. 2016;23(6):915-926. doi: 10.1038/cdd.2015.172. DOI: https://doi.org/10.1038/cdd.2015.172

Yatim N, Cullen S, Albert ML. Dying cells actively regulate adaptive immune responses. Nat Rev Immunol. 2017;17(4):262-275. doi: 10.1038/nri.2017.9. DOI: https://doi.org/10.1038/nri.2017.9

Saleh T, Cuttino L, Gewirtz DA. Autophagy is not uniformly cytoprotective: a personalized medicine approach for autophagy inhibition as a therapeutic strategy in non-small cell lung cancer. Biochim Biophys Acta. 2016;1860(10):2130-216. doi: 10.1016/j.bbagen.2016.06.012. DOI: https://doi.org/10.1016/j.bbagen.2016.06.012

Anding AL, Baehrecke EH. Autophagy in cell life and cell death. Curr Top Dev Biol. 2015;114:67-91. doi: 10.1016/bs.ctdb.2015.07.012. DOI: https://doi.org/10.1016/bs.ctdb.2015.07.012

Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov. 2017;16(7):487-511. doi: 10.1038/nrd.2017.22. DOI: https://doi.org/10.1038/nrd.2017.22

Yoshida GJ. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. J Hematol Oncol. 2017;10(1):67. doi: 10.1186/s13045-017-0436-9. DOI: https://doi.org/10.1186/s13045-017-0436-9

De Amicis F, Guido C, Santoro M, Giordano F, Donà A, Rizza P, et al. Ligand activated progesterone receptor B drives autophagy-senescence transition through a Beclin-1/Bcl-2 dependent mechanism in human breast cancer cells. Oncotarget. 2016;7(36):57955-57969. doi: 10.18632/oncotarget.10799. DOI: https://doi.org/10.18632/oncotarget.10799

Giordano F, Montalto FI, Panno ML, Andò S, De Amicis F. A Notch inhibitor plus resveratrol induced blockade of autophagy drives glioblastoma cell death by promoting a switch to apoptosis. Am J Cancer Res. 2021;11(12):5933-5950. PMID: 35018234.

Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation. Nature. 2015;517(7534):311-320. doi: 10.1038/nature14191. DOI: https://doi.org/10.1038/nature14191

Kaiser WJ, Sridharan H, Huang C, Mandal P, Upton JW, Gough PJ, et al. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J Biol Chem. 2013;288(43):31268-1279. doi: 10.1074/jbc.M113.462341. DOI: https://doi.org/10.1074/jbc.M113.462341

Chen D, Tong J, Yang L, Wei L, Stolz DB, Yu J, et al. PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors. Proc Natl Acad Sci U S A. 2018;115(15):3930-3935. doi: 10.1073/pnas.1717190115. DOI: https://doi.org/10.1073/pnas.1717190115

Sun X, Yin J, Starovasnik MA, Fairbrother WJ, Dixit VM. Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3. J Biol Chem. 2002;277(11):9505-9511. doi: 10.1074/jbc.M109488200. DOI: https://doi.org/10.1074/jbc.M109488200

He S, Wang L, Miao L, Wang T, Du F, Zhao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137(6):1100-1111. doi: 10.1016/j.cell.2009.05.021. DOI: https://doi.org/10.1016/j.cell.2009.05.021

Sun L, Wang H, Wang Z, He S, Chen S, Liao D, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148(1-2):213-227. doi: 10.1016/j.cell.2011.11.031. DOI: https://doi.org/10.1016/j.cell.2011.11.031

Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc Natl Acad Sci U S A. 2012;109(14):5322-5327. doi: 10.1073/pnas.1200012109. DOI: https://doi.org/10.1073/pnas.1200012109

Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG, Alvarez-Diaz S, et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity. 2013;39(3):443-453. doi: 10.1016/j.immuni.2013.06.018. DOI: https://doi.org/10.1016/j.immuni.2013.06.018

Tong X, Tang R, Xiao M, Xu J, Wang W, Zhang B, et al. Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research. J Hematol Oncol. 2022;15(1):174. doi: 10.1186/s13045-022-01392-3. DOI: https://doi.org/10.1186/s13045-022-01392-3

Miller DR, Cramer SD, Thorburn A. The interplay of autophagy and non-apoptotic cell death pathways. Int Rev Cell Mol Biol. 2020;352:159-187. doi: 10.1016/bs.ircmb.2019.12.004. DOI: https://doi.org/10.1016/bs.ircmb.2019.12.004

Galluzzi L, Kepp O, Chan FK, Kroemer G. Necroptosis: Mechanisms and relevance to disease. Annu Rev Pathol. 2017;12:103-130. doi: 10.1146/annurev-pathol-052016-100247. DOI: https://doi.org/10.1146/annurev-pathol-052016-100247

Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1(2):112-119. doi: 10.1038/nchembio711. DOI: https://doi.org/10.1038/nchembio711

Liu X, Zhou M, Mei L, Ruan J, Hu Q, Peng J, et al. Key roles of necroptotic factors in promoting tumor growth. Oncotarget. 2016;7(16):22219-22233. doi: 10.18632/oncotarget.7924. DOI: https://doi.org/10.18632/oncotarget.7924

Koo GB, Morgan MJ, Lee DG, Kim WJ, Yoon JH, Koo JS, et al. Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res. 2015;25(6):707-725. doi: 10.1038/cr.2015.56. DOI: https://doi.org/10.1038/cr.2015.56

Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23(3):369-379. doi: 10.1038/cdd.2015.158. DOI: https://doi.org/10.1038/cdd.2015.158

Yang WS, Stockwell BR. Ferroptosis: Death by lipid peroxidation. Trends Cell Biol. 2016;26(3):165-176. doi: 10.1016/j.tcb.2015.10.014. DOI: https://doi.org/10.1016/j.tcb.2015.10.014

Dixon SJ. Ferroptosis: bug or feature? Immunol Rev. 2017;277(1):150-157. doi: 10.1111/imr.12533. DOI: https://doi.org/10.1111/imr.12533

Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci. 2016;73(11-12):2195-2209. doi: 10.1007/s00018-016-2194-1. DOI: https://doi.org/10.1007/s00018-016-2194-1

Gaschler MM, Andia AA, Liu H, Csuka JM, Hurlocker B, Vaiana CA, et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol. 2018;14(5):507-515. doi: 10.1038/s41589-018-0031-6. DOI: https://doi.org/10.1038/s41589-018-0031-6

Qi X, Li Q, Che X, Wang Q, Wu G. Application of regulatory cell death in cancer: Based on targeted therapy and immunotherapy. Front Immunol. 2022;13:837293. doi: 10.3389/fimmu.2022.837293. DOI: https://doi.org/10.3389/fimmu.2022.837293

Mou Y, Wang J, Wu J, He D, Zhang C, Duan C, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. 2019;12(1):34. doi: 10.1186/s13045-019-0720-y. DOI: https://doi.org/10.1186/s13045-019-0720-y

Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13(1):81-90. doi: 10.1038/nchembio.2238. DOI: https://doi.org/10.1038/nchembio.2238

Feng H, Stockwell BR. Unsolved mysteries: How does lipid peroxidation cause ferroptosis? PLoS Biol. 2018;16(5):e2006203. doi: 10.1371/journal.pbio.2006203. DOI: https://doi.org/10.1371/journal.pbio.2006203

Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060-1072. doi: 10.1016/j.cell.2012.03.042. DOI: https://doi.org/10.1016/j.cell.2012.03.042

Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16(12):1180-1191. doi: 10.1038/ncb3064. DOI: https://doi.org/10.1038/ncb3064

Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693-698. doi: 10.1038/s41586-019-1707-0.

Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693-698. doi: 10.1038/s41586-019-1707-0. DOI: https://doi.org/10.1038/s41586-019-1707-0

Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547(7664):453-457. doi: 10.1038/nature23007. DOI: https://doi.org/10.1038/nature23007

Zhang C, Liu X, Jin S, Chen Y, Guo R. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Mol Cancer. 2022;21(1):47. doi: 10.1186/s12943-022-01530-y. DOI: https://doi.org/10.1186/s12943-022-01530-y

Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526(7575):660-665. doi: 10.1038/nature15514. DOI: https://doi.org/10.1038/nature15514

Qiu S, Liu J, Xing F. 'Hints' in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death. Cell Death Differ. 2017;24(4):588-596. doi: 10.1038/cdd.2017.24. DOI: https://doi.org/10.1038/cdd.2017.24

Jorgensen I, Miao EA. Pyroptotic cell death defends against intracellular pathogens. Immunol Rev. 2015;265(1):130-142. doi: 10.1111/imr.12287. DOI: https://doi.org/10.1111/imr.12287

Shi J, Gao W, Shao F. Pyroptosis: Gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci. 2017;42(4):245-254. doi: 10.1016/j.tibs.2016.10.004. DOI: https://doi.org/10.1016/j.tibs.2016.10.004

Yang J, Zhao Y, Shao F. Non-canonical activation of inflammatory caspases by cytosolic LPS in innate immunity. Curr Opin Immunol. 2015;32:78-83. doi: 10.1016/j.coi.2015.01.007. DOI: https://doi.org/10.1016/j.coi.2015.01.007

Franchi L, Eigenbrod T, Muñoz-Planillo R, Nuñez G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol. 2009;10(3):241-247. doi: 10.1038/ni.1703. DOI: https://doi.org/10.1038/ni.1703

Aziz M, Jacob A, Wang P. Revisiting caspases in sepsis. Cell Death Dis. 2014;5(11):e1526. doi: 10.1038/cddis.2014.488. DOI: https://doi.org/10.1038/cddis.2014.488

Hsu SK, Li CY, Lin IL, Syue WJ, Chen YF, Cheng KC, et al. Inflammation-related pyroptosis, a novel programmed cell death pathway, and its crosstalk with immune therapy in cancer treatment. Theranostics. 2021;11(18):8813-8835. doi: 10.7150/thno.62521. DOI: https://doi.org/10.7150/thno.62521

Wang Y, Gao W, Shi X, Ding J, Liu W, He H, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017;547(7661):99-103. doi: 10.1038/nature22393. DOI: https://doi.org/10.1038/nature22393

Fang Y, Tian S, Pan Y, Li W, Wang Q, Tang Y, et al. Pyroptosis: A new frontier in cancer. Biomed Pharmacother. 2020;121:109595. doi: 10.1016/j.biopha.2019.109595. DOI: https://doi.org/10.1016/j.biopha.2019.109595

Zhou Z, He H, Wang K, Shi X, Wang Y, Su Y, et al. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science. 2020;368(6494):eaaz7548. doi: 10.1126/science.aaz7548. DOI: https://doi.org/10.1126/science.aaz7548

Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017;17(2):97-111. doi: 10.1038/nri.2016.107. DOI: https://doi.org/10.1038/nri.2016.107

Green DR. The coming decade of cell death research: Five riddles. Cell. 2019;177(5):1094-1107. doi: 10.1016/j.cell.2019.04.024. DOI: https://doi.org/10.1016/j.cell.2019.04.024

Galluzzi L, Vitale I, Warren S, Adjemian S, Agostinis P, Martinez AB, et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J Immunother Cancer. 2020;8(1):e000337corr1. doi: 10.1136/jitc-2019-000337corr1. DOI: https://doi.org/10.1136/jitc-2019-000337corr1

Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005;202(12):1691-1701. doi: 10.1084/jem.20050915. DOI: https://doi.org/10.1084/jem.20050915

Hu M, Yang J, Qu L, Deng X, Duan Z, Fu R, et al. Ginsenoside Rk1 induces apoptosis and downregulates the expression of PD-L1 by targeting the NF-κB pathway in lung adenocarcinoma. Food Funct. 2020;11(1):456-471. doi: 10.1039/c9fo02166c. DOI: https://doi.org/10.1039/C9FO02166C

Peng F, Liao M, Qin R, Zhu S, Peng C, Fu L, et al. Regulated cell death (RCD) in cancer: key pathways and targeted therapies. Signal Transduct Target Ther. 2022;7(1):286. doi: 10.1038/s41392-022-01110-y. DOI: https://doi.org/10.1038/s41392-022-01110-y

Liu S, Luo W, Wang Y. Emerging role of PARP-1 and PARthanatos in ischemic stroke. J Neurochem. 2022;160(1):74-87. doi: 10.1111/jnc.15464. DOI: https://doi.org/10.1111/jnc.15464

Yang L, Guttman L, Dawson VL, Dawson TM. Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke. Biochem Pharmacol. 2024;228:116174. doi: 10.1016/j.bcp.2024.116174. DOI: https://doi.org/10.1016/j.bcp.2024.116174

D'Amico M, De Amicis F. Challenges of regulated cell death: Implications for therapy resistance in cancer. Cells. 2024;13(13):1083. doi: 10.3390/cells13131083. DOI: https://doi.org/10.3390/cells13131083

Wang Y, Luo W, Wang Y. PARP-1 and its associated nucleases in DNA damage response. DNA Repair (Amst). 2019;81:102651. doi: 10.1016/j.dnarep.2019.102651. DOI: https://doi.org/10.1016/j.dnarep.2019.102651

Delettre C, Yuste VJ, Moubarak RS, Bras M, Lesbordes-Brion JC, Petres S, et al. AIFsh, a novel apoptosis-inducing factor (AIF) pro-apoptotic isoform with potential pathological relevance in human cancer. J Biol Chem. 2006;281(10):6413-6427. doi: 10.1074/jbc.M509884200. DOI: https://doi.org/10.1074/jbc.M509884200

Wang H, Yu SW, Koh DW, Lew J, Coombs C, Bowers W, et al. Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death. J Neurosci. 2004;24(48):10963-10973. doi: 10.1523/JNEUROSCI.3461-04.2004. DOI: https://doi.org/10.1523/JNEUROSCI.3461-04.2004

Shimizu K, Inuzuka H, Tokunaga F. The interplay between cell death and senescence in cancer. Semin Cancer Biol. 2025;108:1-16. doi: 10.1016/j.semcancer.2024.11.001. DOI: https://doi.org/10.1016/j.semcancer.2024.11.001

Wang S, Guo S, Guo J, Du Q, Wu C, Wu Y, et al. Cell death pathways: molecular mechanisms and therapeutic targets for cancer. MedComm (2020). 2024;5(9):e693. doi: 10.1002/mco2.693. DOI: https://doi.org/10.1002/mco2.693

Glytsou C, Chen X, Zacharioudakis E, Al-Santli W, Zhou H, Nadorp B, et al. Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia. Cancer Discov. 2023;13(7):1656-1677. doi: 10.1158/2159-8290.CD-22-0601. DOI: https://doi.org/10.1158/2159-8290.CD-22-0601

Valentini E, Di Martile M, Brignone M, Di Caprio M, Manni I, Chiappa M, et al. Bcl-2 family inhibitors sensitize human cancer models to therapy. Cell Death Dis. 2023;14(7):441. doi: 10.1038/s41419-023-05963-1. DOI: https://doi.org/10.1038/s41419-023-05963-1

Ohgino K, Terai H, Yasuda H, Nukaga S, Hamamoto J, Tani T, et al. Intracellular levels of reactive oxygen species correlate with ABT-263 sensitivity in non-small-cell lung cancer cells. Cancer Sci. 2020;111(10):3793-3801. doi: 10.1111/cas.14569. DOI: https://doi.org/10.1111/cas.14569

Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008;68(9):3421-3428. doi: 10.1158/0008-5472.CAN-07-5836. DOI: https://doi.org/10.1158/0008-5472.CAN-07-5836

Goy A, Hernandez-Ilzaliturri FJ, Kahl B, Ford P, Protomastro E, Berger M. A phase I/II study of the pan Bcl-2 inhibitor obatoclax mesylate plus bortezomib for relapsed or refractory mantle cell lymphoma. Leuk Lymphoma. 2014;55(12):2761-278. doi: 10.3109/10428194.2014.907891. DOI: https://doi.org/10.3109/10428194.2014.907891

Pukac L, Kanakaraj P, Humphreys R, Alderson R, Bloom M, Sung C, et al. HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Br J Cancer. 2005;92(8):1430-1441. doi: 10.1038/sj.bjc.6602487. DOI: https://doi.org/10.1038/sj.bjc.6602487

Merchant MS, Geller JI, Baird K, Chou AJ, Galli S, Charles A, et al. Phase I trial and pharmacokinetic study of lexatumumab in pediatric patients with solid tumors. J Clin Oncol. 2012;30(33):4141-4147. doi: 10.1200/JCO.2012.44.1055. DOI: https://doi.org/10.1200/JCO.2012.44.1055

von Pawel J, Harvey JH, Spigel DR, Dediu M, Reck M, Cebotaru CL, et al. Phase II trial of mapatumumab, a fully human agonist monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer. Clin Lung Cancer. 2014;15(3):188-196. doi: 10.1016/j.cllc.2013.12.005. DOI: https://doi.org/10.1016/j.cllc.2013.12.005

Kim TH, Youn YS, Jiang HH, Lee S, Chen X, Lee KC. PEGylated TNF-related apoptosis-inducing ligand (TRAIL) analogues: pharmacokinetics and antitumor effects. Bioconjug Chem. 2011;22(8):1631-1637. doi: 10.1021/bc200187k. DOI: https://doi.org/10.1021/bc200187k

Phillips DC, Buchanan FG, Cheng D, Solomon LR, Xiao Y, Xue J, et al. Hexavalent TRAIL fusion protein eftozanermin alfa optimally clusters apoptosis-inducing TRAIL receptors to induce on-target antitumor activity in solid tumors. Cancer Res. 2021;81(12):3402-3414. doi: 10.1158/0008-5472.CAN-20-2178. DOI: https://doi.org/10.1158/0008-5472.CAN-20-2178

LoRusso P, Ratain MJ, Doi T, Rasco DW, de Jonge MJA, Moreno V, et al. Eftozanermin alfa (ABBV-621) monotherapy in patients with previously treated solid tumors: findings of a phase 1, first-in-human study. Invest New Drugs. 2022;40(4):762-772. doi: 10.1007/s10637-022-01247-1. DOI: https://doi.org/10.1007/s10637-022-01247-1

Tian X, Srinivasan PR, Tajiknia V, Sanchez Sevilla Uruchurtu AF, Seyhan AA, Carneiro BA, et al. Targeting apoptotic pathways for cancer therapy. J Clin Invest. 2024;134(14):e179570. doi: 10.1172/JCI179570. DOI: https://doi.org/10.1172/JCI179570

Lee HO, Mustafa A, Hudes GR, Kruger WD. Hydroxychloroquine destabilizes phospho-S6 in human renal carcinoma cells. PLoS One. 2015;10(7):e0131464. doi: 10.1371/journal.pone.0131464. DOI: https://doi.org/10.1371/journal.pone.0131464

Xu R, Ji Z, Xu C, Zhu J. The clinical value of using chloroquine or hydroxychloroquine as autophagy inhibitors in the treatment of cancers: A systematic review and meta-analysis. Medicine (Baltimore). 2018;97(46):e12912. doi: 10.1097/MD.0000000000012912. DOI: https://doi.org/10.1097/MD.0000000000012912

Liu ZY, Wu B, Guo YS, Zhou YH, Fu ZG, Xu BQ, et al. Necrostatin-1 reduces intestinal inflammation and colitis-associated tumorigenesis in mice. Am J Cancer Res. 2015;5(10):3174-3185. PMID: 26693068.

Cao L, Mu W. Necrostatin-1 and necroptosis inhibition: Pathophysiology and therapeutic implications. Pharmacol Res. 2021;163:105297. doi: 10.1016/j.phrs.2020.105297. DOI: https://doi.org/10.1016/j.phrs.2020.105297

Gong Y, Fan Z, Luo G, Yang C, Huang Q, Fan K, et al. The role of necroptosis in cancer biology and therapy. Mol Cancer. 2019;18(1):100. doi: 10.1186/s12943-019-1029-8. DOI: https://doi.org/10.1186/s12943-019-1029-8

Zhou XY, Lin B, Chen W, Cao RQ, Guo Y, Said A, et al. The brain protection of MLKL inhibitor necrosulfonamide against focal ischemia/reperfusion injury associating with blocking the nucleus and nuclear envelope translocation of MLKL and RIP3K. Front Pharmacol. 2023;14:1157054. doi: 10.3389/fphar.2023.1157054. DOI: https://doi.org/10.3389/fphar.2023.1157054

Chen GQ, Benthani FA, Wu J, Liang D, Bian ZX, Jiang X. Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis. Cell Death Differ. 2020;27(1):242-254. doi: 10.1038/s41418-019-0352-3. DOI: https://doi.org/10.1038/s41418-019-0352-3

Du J, Wang T, Li Y, Zhou Y, Wang X, Yu X, et al. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic Biol Med. 2019;131:356-369. doi: 10.1016/j.freeradbiomed.2018.12.011. DOI: https://doi.org/10.1016/j.freeradbiomed.2018.12.011

Jiang M, Qiao M, Zhao C, Deng J, Li X, Zhou C. Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers. Transl Lung Cancer Res. 2020;9(4):1569-1584. doi: 10.21037/tlcr-20-341. DOI: https://doi.org/10.21037/tlcr-20-341

Booth LA, Roberts JL, Dent P. The role of cell signaling in the crosstalk between autophagy and apoptosis in the regulation of tumor cell survival in response to sorafenib and neratinib. Semin Cancer Biol. 2020;66:129-139. doi: 10.1016/j.semcancer.2019.10.013. DOI: https://doi.org/10.1016/j.semcancer.2019.10.013

Feng J, Lu PZ, Zhu GZ, Hooi SC, Wu Y, Huang XW, et al. ACSL4 is a predictive biomarker of sorafenib sensitivity in hepatocellular carcinoma. Acta Pharmacol Sin. 2021;42(1):160-170. doi: 10.1038/s41401-020-0439-x. DOI: https://doi.org/10.1038/s41401-020-0439-x

Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. 2014;3:e02523. doi: 10.7554/eLife.02523. DOI: https://doi.org/10.7554/eLife.02523

Fonseca-Nunes A, Jakszyn P, Agudo A. Iron and cancer risk--a systematic review and meta-analysis of the epidemiological evidence. Cancer Epidemiol Biomarkers Prev. 2014;23(1):12-31. doi: 10.1158/1055-9965.EPI-13-0733. DOI: https://doi.org/10.1158/1055-9965.EPI-13-0733

Tsoi J, Robert L, Paraiso K, Galvan C, Sheu KM, Lay J, et al. Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress. Cancer Cell. 2018;33(5):890-904.e5. doi: 10.1016/j.ccell.2018.03.017. DOI: https://doi.org/10.1016/j.ccell.2018.03.017

Wu F, Huang F, Jiang N, Su J, Yao S, Liang B, et al. Identification of ferroptosis related genes and pathways in prostate cancer cells under erastin exposure. BMC Urol. 2024;24(1):78. doi: 10.1186/s12894-024-01472-1. DOI: https://doi.org/10.1186/s12894-024-01472-1

Zheng Z, Bian Y, Zhang Y, Ren G, Li G. Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis. Cell Cycle. 2020;19(10):1089-1104. doi: 10.1080/15384101.2020.1743911. DOI: https://doi.org/10.1080/15384101.2020.1743911

Wang L, Li K, Lin X, Yao Z, Wang S, Xiong X, et al. Metformin induces human esophageal carcinoma cell pyroptosis by targeting the miR-497/PELP1 axis. Cancer Lett. 2019;450:22-31. doi: 10.1016/j.canlet.2019.02.014. DOI: https://doi.org/10.1016/j.canlet.2019.02.014

Rose M, Burgess JT, O'Byrne K, Richard DJ, Bolderson E. PARP inhibitors: Clinical relevance, mechanisms of action and tumor resistance. Front Cell Dev Biol. 2020;8:564601. doi: 10.3389/fcell.2020.564601. DOI: https://doi.org/10.3389/fcell.2020.564601

Shimony S, Rozental A, Bewersdorf JP, Goldberg AD, Stein EM, Grimshaw AA, et al. Investigational venetoclax combination therapy in acute myeloid leukemia - a systematic review and meta-analysis. Haematologica. 2022;107(12):2955-2960. doi: 10.3324/haematol.2022.281453. DOI: https://doi.org/10.3324/haematol.2022.281453

Joly F, Fabbro M, Follana P, Lequesne J, Medioni J, Lesoin A, et al. A phase II study of Navitoclax (ABT-263) as single agent in women heavily pretreated for recurrent epithelial ovarian cancer: The MONAVI - GINECO study. Gynecol Oncol. 2022;165(1):30-39. doi: 10.1016/j.ygyno.2022.01.021. DOI: https://doi.org/10.1016/j.ygyno.2022.01.021

Ciuleanu T, Bazin I, Lungulescu D, Miron L, Bondarenko I, Deptala A, et al. A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma. Ann Oncol. 2016;27(4):680-687. doi: 10.1093/annonc/mdw004. DOI: https://doi.org/10.1093/annonc/mdw004

Kindler HL, Richards DA, Garbo LE, Garon EB, Stephenson JJ, Rocha-Lima CM, et al. A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Ann Oncol. 2012;23(11):2834-2842. doi: 10.1093/annonc/mds142. DOI: https://doi.org/10.1093/annonc/mds142

Rocha Lima CM, Bayraktar S, Flores AM, MacIntyre J, Montero A, Baranda JC, et al. Phase Ib study of drozitumab combined with first-line mFOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer. Cancer Invest. 2012;30(10):727-731. doi: 10.3109/07357907.2012.732163. DOI: https://doi.org/10.3109/07357907.2012.732163

Agalakova NI. Chloroquine and chemotherapeutic compounds in experimental cancer treatment. Int J Mol Sci. 2024;25(2):945. doi: 10.3390/ijms25020945. DOI: https://doi.org/10.3390/ijms25020945

Du J, Wang X, Li Y, Ren X, Zhou Y, Hu W, et al. DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism. Cell Death Dis. 2021;12(7):705. doi: 10.1038/s41419-021-03996-y. DOI: https://doi.org/10.1038/s41419-021-03996-y

Sun J, Wei Q, Zhou Y, Wang J, Liu Q, Xu H. A systematic analysis of FDA-approved anticancer drugs. BMC Syst Biol. 2017;11(Suppl 5):87. doi: 10.1186/s12918-017-0464-7. DOI: https://doi.org/10.1186/s12918-017-0464-7

Chen H, Wang C, Liu Z, He X, Tang W, He L, et al. Ferroptosis and its multifaceted role in cancer: Mechanisms and therapeutic approach. Antioxidants (Basel). 2022;11(8):1504. doi: 10.3390/antiox11081504. DOI: https://doi.org/10.3390/antiox11081504

Keldsen N, Havsteen H, Vergote I, Bertelsen K, Jakobsen A. Altretamine (hexamethylmelamine) in the treatment of platinum-resistant ovarian cancer: a phase II study. Gynecol Oncol. 2003;88(2):118-122. doi: 10.1016/s0090-8258(02)00103-8. DOI: https://doi.org/10.1016/S0090-8258(02)00103-8

Roh JL, Kim EH, Jang HJ, Park JY, Shin D. Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer. Cancer Lett. 2016;381(1):96-103. doi: 10.1016/j.canlet.2016.07.035. DOI: https://doi.org/10.1016/j.canlet.2016.07.035

Galluzzi L, Humeau J, Buqué A, Zitvogel L, Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 2020;17(12):725-741. doi: 10.1038/s41571-020-0413-z. DOI: https://doi.org/10.1038/s41571-020-0413-z

Rodriguez-Ruiz ME, Vitale I, Harrington KJ, Melero I, Galluzzi L. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment. Nat Immunol. 2020;21(2):120-134. doi: 10.1038/s41590-019-0561-4. DOI: https://doi.org/10.1038/s41590-019-0561-4

Pozzi C, Cuomo A, Spadoni I, Magni E, Silvola A, Conte A, et al. The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death. Nat Med. 2016;22(6):624-631. doi: 10.1038/nm.4078. DOI: https://doi.org/10.1038/nm.4078

Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T, et al. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 2012;31(5):1062-79. doi: 10.1038/emboj.2011.497. DOI: https://doi.org/10.1038/emboj.2011.497

Zhou H, Forveille S, Sauvat A, Yamazaki T, Senovilla L, Ma Y, et al. The oncolytic peptide LTX-315 triggers immunogenic cell death. Cell Death Dis. 2016;7(3):e2134. doi: 10.1038/cddis.2016.47. DOI: https://doi.org/10.1038/cddis.2016.47

Bommareddy PK, Shettigar M, Kaufman HL. Integrating oncolytic viruses in combination cancer immunotherapy. Nat Rev Immunol. 2018;18(8):498-513. doi: 10.1038/s41577-018-0014-6. DOI: https://doi.org/10.1038/s41577-018-0014-6

Shah M, Green J, Hudacko R, Cohen AJ. Clinical response to olaparib in a patient with leptomeningeal carcinomatosis in newly diagnosed breast cancer with germline BRCA2 mutation. JCO Precis Oncol. 2024;8:e2400063. doi: 10.1200/PO.24.00063. DOI: https://doi.org/10.1200/PO.24.00063

Wu X, Zhu J, Yin R, Yang J, Liu J, Wang J, et al. Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial. EClinicalMedicine. 2024;72:102629. doi: 10.1016/j.eclinm.2024.102629. DOI: https://doi.org/10.1016/j.eclinm.2024.102629

Sayyid RK, Bernardino R, Chavarriaga J, Gleave A, Kumar R, Fleshner NE. Rucaparib monotherapy in the heavily pre-treated metastatic castrate-resistant prostate cancer setting: practical considerations and alternate treatment approaches. Transl Androl Urol. 2024;13(5):884-888. doi: 10.21037/tau-23-671. DOI: https://doi.org/10.21037/tau-23-671