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Pyroptosis and pyroptosis-inducing cancer drugs

Abstract

Pyroptosis, an inflammatory form of lytic cell death, is a type of cell death mediated by the gasdermin (GSDM) protein family. Upon recognizing exogenous or endogenous signals, cells undergo inflammasome assembly, GSDM cleavage, the release of proinflammatory cytokines and other cellular contents, eventually leading to inflammatory cell death. In this review, we discuss the roles of the GSDM family for anti-cancer functions and various antitumor drugs that could activate the pyroptosis pathways.

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Fig. 1: Roles of caspase-1 and −11 in GSDMD-mediated pyroptosis.
Fig. 2: The activation of GSDMD followed by transmembrane pore formation.
Fig. 3: Sequence and structural alignment of caspase-1 (green) and caspase-11 (cyan) without CARD domain.
Fig. 4: The schematic view of drug-induced pyroptosis in cancer cells.
Fig. 5: PANoptosis during the infection of influenza A virus.

References

  1. Lieberman J, Wu H, Kagan JC. Gasdermin D activity in inflammation and host defense. Sci Immunol. 2019;4:eaav1447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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;526:660–5.

    Article  CAS  PubMed  Google Scholar 

  3. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526:666–71.

    Article  CAS  PubMed  Google Scholar 

  4. 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:eaaz7548.

    Article  CAS  PubMed  Google Scholar 

  5. Zhang Z, Zhang Y, Xia S, Kong Q, Li S, Liu X, et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature. 2020;579:415–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hou J, Zhao R, Xia W, Chang CW, You Y, Hsu JM, et al. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat Cell Biol. 2020;22:1264–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yu J, Kang MJ, Kim BJ, Kwon JW, Song YH, Choi WA, et al. Polymorphisms in GSDMA and GSDMB are associated with asthma susceptibility, atopy and BHR. Pediatr Pulmonol. 2011;46:701–8.

    Article  PubMed  Google Scholar 

  8. Chao KL, Kulakova L, Herzberg O. Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein. Proc Natl Acad Sci USA. 2017;114:E1128–E37.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Tanaka S, Mizushina Y, Kato Y, Tamura M, Shiroishi T. Functional conservation of Gsdma cluster genes specifically duplicated in the mouse genome. G3 (Bethesda). 2013;3:1843–50.

    Article  CAS  Google Scholar 

  10. Ruge F, Glavini A, Gallimore AM, Richards HE, Thomas CP, O’Donnell VB, et al. Delineating immune-mediated mechanisms underlying hair follicle destruction in the mouse mutant defolliculated. J Invest Dermatol. 2011;131:572–9.

    Article  CAS  PubMed  Google Scholar 

  11. Saeki N, Usui T, Aoyagi K, Kim DH, Sato M, Mabuchi T, et al. Distinctive expression and function of four GSDM family genes (GSDMA-D) in normal and malignant upper gastrointestinal epithelium. Genes Chromosomes Cancer. 2009;48:261–71.

    Article  CAS  PubMed  Google Scholar 

  12. Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 2016;535:111–6.

    Article  CAS  PubMed  Google Scholar 

  13. Ruan J, Xia S, Liu X, Lieberman J, Wu H. Cryo-EM structure of the gasdermin A3 membrane pore. Nature. 2018;557:62–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zou J, Zheng Y, Huang Y, Tang D, Kang R, Chen R. The versatile gasdermin family: their function and roles in diseases. Front Immunol. 2021;12:751533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang Q, Wang Y, Ding J, Wang C, Zhou X, Gao W, et al. A bioorthogonal system reveals antitumour immune function of pyroptosis. Nature. 2020;579:421–6.

    Article  CAS  PubMed  Google Scholar 

  16. Panganiban RA, Sun M, Dahlin A, Park HR, Kan M, Himes BE, et al. A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis. J Allergy Clin Immunol. 2018;142:1469–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen Q, Shi P, Wang Y, Zou D, Wu X, Wang D, et al. GSDMB promotes non-canonical pyroptosis by enhancing caspase-4 activity. J Mol Cell Biol. 2019;11:496–508.

    Article  CAS  PubMed  Google Scholar 

  18. Miguchi M, Hinoi T, Shimomura M, Adachi T, Saito Y, Niitsu H, et al. Gasdermin C is upregulated by inactivation of transforming growth factor beta receptor type II in the presence of mutated Apc, promoting colorectal cancer proliferation. PLoS One. 2016;11:e0166422.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Watabe K, Ito A, Asada H, Endo Y, Kobayashi T, Nakamoto K, et al. Structure, expression and chromosome mapping of MLZE, a novel gene which is preferentially expressed in metastatic melanoma cells. Jpn J Cancer Res. 2001;92:140–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Qiu S, Hu Y, Dong S. Pan-cancer analysis reveals the expression, genetic alteration and prognosis of pyroptosis key gene GSDMD. Int Immunopharmacol. 2021;101:108270.

    Article  CAS  PubMed  Google Scholar 

  21. Van Laer L, Huizing EH, Verstreken M, van Zuijlen D, Wauters JG, Bossuyt PJ, et al. Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nat Genet. 1998;20:194–7.

    Article  PubMed  Google Scholar 

  22. Cheng J, Han DY, Dai P, Sun HJ, Tao R, Sun Q, et al. A novel DFNA5 mutation, IVS8+4 A>G, in the splice donor site of intron 8 causes late-onset non-syndromic hearing loss in a Chinese family. Clin Genet. 2007;72:471–7.

    Article  CAS  PubMed  Google Scholar 

  23. Rogers C, Fernandes-Alnemri T, Mayes L, Alnemri D, Cingolani G, Alnemri ES. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat Commun. 2017;8:14128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Xu WF, Zhang Q, Ding CJ, Sun HY, Che Y, Huang H, et al. Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure. Acta Pharmacol Sin. 2021;42:68–76.

    Article  PubMed  CAS  Google Scholar 

  25. Zhang CC, Li CG, Wang YF, Xu LH, He XH, Zeng QZ, et al. Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation. Apoptosis. 2019;24:312–25.

    Article  CAS  PubMed  Google Scholar 

  26. Yu J, Li S, Qi J, Chen Z, Wu Y, Guo J, et al. Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells. Cell Death Dis. 2019;10:193.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Akino K, Toyota M, Suzuki H, Imai T, Maruyama R, Kusano M, et al. Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer. Cancer Sci. 2007;98:88–95.

    Article  CAS  PubMed  Google Scholar 

  28. Rogers C, Erkes DA, Nardone A, Aplin AE, Fernandes-Alnemri T, Alnemri ES. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat Commun. 2019;10:1689.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Ibrahim J, Op de Beeck K, Fransen E, Croes L, Beyens M, Suls A, et al. Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer. Cancer Med. 2019;8:2133–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov. 2018;17:688.

    Article  CAS  PubMed  Google Scholar 

  31. Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–32.

    Article  CAS  PubMed  Google Scholar 

  33. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440:228–32.

    Article  CAS  PubMed  Google Scholar 

  34. Hise AG, Tomalka J, Ganesan S, Patel K, Hall BA, Brown GD, et al. An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. Cell Host Microbe. 2009;5:487–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kumar H, Kumagai Y, Tsuchida T, Koenig PA, Satoh T, Guo Z, et al. Involvement of the NLRP3 inflammasome in innate and humoral adaptive immune responses to fungal beta-glucan. J Immunol. 2009;183:8061–7.

    Article  CAS  PubMed  Google Scholar 

  36. Muruve DA, Petrilli V, Zaiss AK, White LR, Clark SA, Ross PJ, et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature. 2008;452:103–7.

    Article  CAS  PubMed  Google Scholar 

  37. Thomas PG, Dash P, Aldridge JR Jr., Ellebedy AH, Reynolds C, Funk AJ, et al. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity. 2009;30:566–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chavarria-Smith J, Vance RE. The NLRP1 inflammasomes. Immunol Rev. 2015;265:22–34.

    Article  CAS  PubMed  Google Scholar 

  39. Taabazuing CY, Griswold AR, Bachovchin DA. The NLRP1 and CARD8 inflammasomes. Immunol Rev. 2020;297:13–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang Y, Cirelli KM, Barros PDC, Sangare LO, Butty V, Hassan MA, et al. Three toxoplasma gondii dense granule proteins are required for induction of Lewis rat macrophage pyroptosis. mBio. 2019;10:e02388–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014;46:1140–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vance RE. The NAIP/NLRC4 inflammasomes. Curr Opin Immunol. 2015;32:84–9.

    Article  CAS  PubMed  Google Scholar 

  43. Tenthorey JL, Kofoed EM, Daugherty MD, Malik HS, Vance RE. Molecular basis for specific recognition of bacterial ligands by NAIP/NLRC4 inflammasomes. Mol Cell. 2014;54:17–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Qu Y, Misaghi S, Newton K, Maltzman A, Izrael-Tomasevic A, Arnott D, et al. NLRP3 recruitment by NLRC4 during Salmonella infection. J Exp Med. 2016;213:877–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mitchell PS, Roncaioli JL, Turcotte EA, Goers L, Chavez RA, Lee AY, et al. NAIP-NLRC4-deficient mice are susceptible to shigellosis. Elife. 2020;9:e59022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cai S, Batra S, Wakamatsu N, Pacher P, Jeyaseelan S. NLRC4 inflammasome-mediated production of IL-1beta modulates mucosal immunity in the lung against gram-negative bacterial infection. J Immunol. 2012;188:5623–35.

    Article  CAS  PubMed  Google Scholar 

  47. Lugrin J, Martinon F. The AIM2 inflammasome: sensor of pathogens and cellular perturbations. Immunol Rev. 2018;281:99–114.

    Article  CAS  PubMed  Google Scholar 

  48. Man SM, Karki R, Kanneganti TD. AIM2 inflammasome in infection, cancer, and autoimmunity: role in DNA sensing, inflammation, and innate immunity. Eur J Immunol. 2016;46:269–80.

    Article  CAS  PubMed  Google Scholar 

  49. Zahid A, Ismail H, Li B, Jin T. Molecular and structural basis of DNA sensors in antiviral innate immunity. Front Immunol. 2020;11:613039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Loeven NA, Medici NP, Bliska JB. The pyrin inflammasome in host-microbe interactions. Curr Opin Microbiol. 2020;54:77–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Heilig R, Broz P. Function and mechanism of the pyrin inflammasome. Eur J Immunol. 2018;48:230–8.

    Article  CAS  PubMed  Google Scholar 

  52. Saavedra PHV, Huang L, Ghazavi F, Kourula S, Vanden Berghe T, Takahashi N, et al. Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis. Nat Commun. 2018;9:4846.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Santos JC, Boucher D, Schneider LK, Demarco B, Dilucca M, Shkarina K, et al. Human GBP1 binds LPS to initiate assembly of a caspase-4 activating platform on cytosolic bacteria. Nat Commun. 2020;11:3276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fisch D, Clough B, Domart MC, Encheva V, Bando H, Snijders AP, et al. Human GBP1 differentially targets salmonella and toxoplasma to license recognition of microbial ligands and caspase-mediated death. Cell Rep. 2020;32:108008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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;547:99–103.

    Article  CAS  PubMed  Google Scholar 

  56. Mulvihill E, Sborgi L, Mari SA, Pfreundschuh M, Hiller S, Muller DJ. Mechanism of membrane pore formation by human gasdermin-D. EMBO J. 2018;37:e98321.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Abreu-Blanco MT, Watts JJ, Verboon JM, Parkhurst SM. Cytoskeleton responses in wound repair. Cell Mol Life Sci. 2012;69:2469–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. McNeil PL, Terasaki M. Coping with the inevitable: how cells repair a torn surface membrane. Nat Cell Biol. 2001;3:E124–9.

    Article  CAS  PubMed  Google Scholar 

  59. Reddy A, Caler EV, Andrews NW. Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. Cell. 2001;106:157–69.

    Article  CAS  PubMed  Google Scholar 

  60. Kayagaki N, Kornfeld OS, Lee BL, Stowe IB, O’Rourke K, Li Q, et al. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature. 2021;591:131–6.

    Article  CAS  PubMed  Google Scholar 

  61. Johnson DC, Taabazuing CY, Okondo MC, Chui AJ, Rao SD, Brown FC, et al. DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. Nat Med. 2018;24:1151–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Johnson DC, Okondo MC, Orth EL, Rao SD, Huang HC, Ball DP, et al. DPP8/9 inhibitors activate the CARD8 inflammasome in resting lymphocytes. Cell Death Dis. 2020;11:628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Linder A, Bauernfried S, Cheng Y, Albanese M, Jung C, Keppler OT, et al. CARD8 inflammasome activation triggers pyroptosis in human T cells. EMBO J. 2020;39:e105071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhong FL, Robinson K, Teo DET, Tan KY, Lim C, Harapas CR, et al. Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding. J Biol Chem. 2018;293:18864–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Li F, Aljahdali I, Ling X. Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study? J Exp Clin Cancer Res. 2019;38:368.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Tang Z, Ji L, Han M, Xie J, Zhong F, Zhang X, et al. Pyroptosis is involved in the inhibitory effect of FL118 on growth and metastasis in colorectal cancer. Life Sci. 2020;257:118065.

    Article  CAS  PubMed  Google Scholar 

  67. He J, Giusti MM. Anthocyanins: natural colorants with health-promoting properties. Annu Rev Food Sci Technol. 2010;1:163–87.

    Article  CAS  PubMed  Google Scholar 

  68. Lin BW, Gong CC, Song HF, Cui YY. Effects of anthocyanins on the prevention and treatment of cancer. Br J Pharmacol. 2017;174:1226–43.

    Article  CAS  PubMed  Google Scholar 

  69. Yue E, Tuguzbaeva G, Chen X, Qin Y, Li A, Sun X, et al. Anthocyanin is involved in the activation of pyroptosis in oral squamous cell carcinoma. Phytomedicine. 2019;56:286–94.

    Article  CAS  PubMed  Google Scholar 

  70. Blanckaert V, Ulmann L, Mimouni V, Antol J, Brancquart L, Chenais B. Docosahexaenoic acid intake decreases proliferation, increases apoptosis and decreases the invasive potential of the human breast carcinoma cell line MDA-MB-231. Int J Oncol. 2010;36:737–42.

    Article  CAS  PubMed  Google Scholar 

  71. Pizato N, Luzete BC, Kiffer L, Correa LH, de Oliveira Santos I, Assumpcao JAF, et al. Omega-3 docosahexaenoic acid induces pyroptosis cell death in triple-negative breast cancer cells. Sci Rep. 2018;8:1952.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Kang KS, Wang P, Yamabe N, Fukui M, Jay T, Zhu BT. Docosahexaenoic acid induces apoptosis in MCF-7 cells in vitro and in vivo via reactive oxygen species formation and caspase 8 activation. PLoS One. 2010;5:e10296.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Graham KL, Zhang JV, Lewen S, Burke TM, Dang T, Zoudilova M, et al. A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease. PLoS One. 2014;9:e112925.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Li S, Wu Y, Yang D, Wu C, Ma C, Liu X, et al. Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis. J Exp Med. 2019;216:2562–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Qiao L, Wu X, Zhang J, Liu L, Sui X, Zhang R, et al. alpha-NETA induces pyroptosis of epithelial ovarian cancer cells through the GSDMD/caspase-4 pathway. FASEB J. 2019;33:12760–7.

    Article  CAS  PubMed  Google Scholar 

  76. Eliopoulos AG, Kerr DJ, Herod J, Hodgkins L, Krajewski S, Reed JC, et al. The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2. Oncogene. 1995;11:1217–28.

    CAS  PubMed  Google Scholar 

  77. Wu M, Wang Y, Yang D, Gong Y, Rao F, Liu R, et al. A PLK1 kinase inhibitor enhances the chemosensitivity of cisplatin by inducing pyroptosis in oesophageal squamous cell carcinoma. EBioMedicine. 2019;41:244–55.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Kwong YL, Todd D. Delicious poison: arsenic trioxide for the treatment of leukemia. Blood. 1997;89:3487–8.

    Article  CAS  PubMed  Google Scholar 

  79. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89:3354–60.

    Article  CAS  PubMed  Google Scholar 

  80. Kinjo K, Kizaki M, Muto A, Fukuchi Y, Umezawa A, Yamato K, et al. Arsenic trioxide (As2O3)-induced apoptosis and differentiation in retinoic acid-resistant acute promyelocytic leukemia model in hGM-CSF-producing transgenic SCID mice. Leukemia. 2000;14:431–8.

    Article  CAS  PubMed  Google Scholar 

  81. Maier NK, Crown D, Liu J, Leppla SH, Moayeri M. Arsenic trioxide and other arsenical compounds inhibit the NLRP1, NLRP3, and NAIP5/NLRC4 inflammasomes. J Immunol. 2014;192:763–70.

    Article  CAS  PubMed  Google Scholar 

  82. Hu J, Dong Y, Ding L, Dong Y, Wu Z, Wang W, et al. Local delivery of arsenic trioxide nanoparticles for hepatocellular carcinoma treatment. Signal Transduct Target Ther. 2019;4:28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Zhao C, Liu Z, Liang G. Promising curcumin-based drug design: mono-carbonyl analogues of curcumin (MACs). Curr Pharm Des. 2013;19:2114–35.

    CAS  PubMed  Google Scholar 

  84. Chen L, Weng B, Li H, Wang H, Li Q, Wei X, et al. A thiopyran derivative with low murine toxicity with therapeutic potential on lung cancer acting through a NF-kappaB mediated apoptosis-to-pyroptosis switch. Apoptosis. 2019;24:74–82.

    Article  CAS  PubMed  Google Scholar 

  85. Bogdan AR, Miyazawa M, Hashimoto K, Tsuji Y. Regulators of iron homeostasis: new players in metabolism, cell death, and disease. Trends Biochem Sci. 2016;41:274–86.

    Article  CAS  PubMed  Google Scholar 

  86. Zhou B, Zhang JY, Liu XS, Chen HZ, Ai YL, Cheng K, et al. Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis. Cell Res. 2018;28:1171–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Soengas MS, Lowe SW. Apoptosis and melanoma chemoresistance. Oncogene. 2003;22:3138–51.

    Article  CAS  PubMed  Google Scholar 

  88. Ashour AA, Abdel-Aziz AA, Mansour AM, Alpay SN, Huo L, Ozpolat B. Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells. Apoptosis. 2014;19:241–58.

    Article  CAS  PubMed  Google Scholar 

  89. Byrne BG, Dubuisson JF, Joshi AD, Persson JJ, Swanson MS. Inflammasome components coordinate autophagy and pyroptosis as macrophage responses to infection. mBio. 2013;4:e00620–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yu P, Wang HY, Tian M, Li AX, Chen XS, Wang XL, et al. Eukaryotic elongation factor-2 kinase regulates the cross-talk between autophagy and pyroptosis in doxorubicin-treated human melanoma cells in vitro. Acta Pharmacol Sin. 2019;40:1237–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Galluzzi L, Vacchelli E, Michels J, Garcia P, Kepp O, Senovilla L, et al. Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses. Oncogene. 2013;32:4995–5004.

    Article  CAS  PubMed  Google Scholar 

  92. Yang W, Liu S, Li Y, Wang Y, Deng Y, Sun W, et al. Pyridoxine induces monocyte-macrophages death as specific treatment of acute myeloid leukemia. Cancer Lett. 2020;492:96–105.

    Article  CAS  PubMed  Google Scholar 

  93. McKeage MJ. Lobaplatin: a new antitumour platinum drug. Expert Opin Investig Drugs. 2001;10:119–28.

    Article  CAS  PubMed  Google Scholar 

  94. Zhou L, Jiang L, Xu M, Liu Q, Gao N, Li P, et al. Miltirone exhibits antileukemic activity by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction pathways. Sci Rep. 2016;6:20585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhang X, Zhang P, An L, Sun N, Peng L, Tang W, et al. Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis. Acta Pharm Sin B. 2020;10:1397–413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Song W, Ma YY, Miao S, Yang RP, Zhu Y, Shu D, et al. Pharmacological actions of miltirone in the modulation of platelet function. Acta Pharmacol Sin. 2019;40:199–207.

    Article  CAS  PubMed  Google Scholar 

  97. 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.

    Article  CAS  PubMed  Google Scholar 

  98. Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, et al. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature. 2014;505:509–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011;479:117–21.

    Article  CAS  PubMed  Google Scholar 

  100. Luo B, Huang F, Liu Y, Liang Y, Wei Z, Ke H, et al. NLRP3 inflammasome as a molecular marker in diabetic cardiomyopathy. Front Physiol. 2017;8:519.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Hu JJ, Liu X, Xia S, Zhang Z, Zhang Y, Zhao J, et al. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat Immunol. 2020;21:736–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Humphries F, Shmuel-Galia L, Ketelut-Carneiro N, Li S, Wang B, Nemmara VV, et al. Succination inactivates gasdermin D and blocks pyroptosis. Science. 2020;369:1633–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang Z, Xu G, Gao Y, Zhan X, Qin N, Fu S, et al. Cardamonin from a medicinal herb protects against LPS-induced septic shock by suppressing NLRP3 inflammasome. Acta Pharm Sin B. 2019;9:734–44.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Lamkanfi M, Mueller JL, Vitari AC, Misaghi S, Fedorova A, Deshayes K, et al. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J Cell Biol. 2009;187:61–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. He H, Jiang H, Chen Y, Ye J, Wang A, Wang C, et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat Commun. 2018;9:2550.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Ye J, Zeng B, Zhong M, Li H, Xu L, Shu J, et al. Scutellarin inhibits caspase-11 activation and pyroptosis in macrophages via regulating PKA signaling. Acta Pharm Sin B. 2021;11:112–26.

    Article  CAS  PubMed  Google Scholar 

  107. Malireddi RKS, Karki R, Sundaram B, Kancharana B, Lee S, Samir P, et al. Inflammatory cell death, PANoptosis, mediated by cytokines in diverse cancer lineages inhibits tumor growth. Immunohorizons. 2021;5:568–80.

    Article  PubMed  CAS  Google Scholar 

  108. Karki R, Sundaram B, Sharma BR, Lee S, Malireddi RKS, Nguyen LN, et al. ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis. Cell Rep. 2021;37:109858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Jiang M, Qi L, Li L, Wu Y, Song D, Li Y. Caspase-8: a key protein of cross-talk signal way in “PANoptosis” in cancer. Int J Cancer. 2021;149:1408–20.

    Article  CAS  PubMed  Google Scholar 

  110. Wang Y, Kanneganti TD. From pyroptosis, apoptosis and necroptosis to PANoptosis: a mechanistic compendium of programmed cell death pathways. Comput Struct Biotechnol J. 2021;19:4641–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Malireddi RKS, Gurung P, Mavuluri J, Dasari TK, Klco JM, Chi H, et al. TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation. J Exp Med. 2018;215:1023–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Malireddi RKS, Gurung P, Kesavardhana S, Samir P, Burton A, Mummareddy H, et al. Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity-independent pyroptosis, apoptosis, necroptosis, and inflammatory disease. J Exp Med. 2020;217:e.20191644.

    Article  CAS  Google Scholar 

  113. Kuriakose T, Man SM, Malireddi RK, Karki R, Kesavardhana S, Place DE, et al. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci Immunol. 2016;1:aag2045.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Zheng M, Karki R, Vogel P, Kanneganti TD. Caspase-6 is a key regulator of innate immunity, inflammasome activation, and host defense. Cell. 2020;181:674–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This publication was made possible by the Arkansas INBRE program (P20 GM103429) and grants from National Heart, Lung and Blood Institute (HL153876, USA) and National Eye Institute (EY030621, USA).

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Correspondence to Hua Zhu or Shanzhi Wang.

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Yang, F., Bettadapura, S.N., Smeltzer, M.S. et al. Pyroptosis and pyroptosis-inducing cancer drugs. Acta Pharmacol Sin 43, 2462–2473 (2022). https://doi.org/10.1038/s41401-022-00887-6

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  • DOI: https://doi.org/10.1038/s41401-022-00887-6

Keywords

  • pyroptosis
  • inflammasome
  • caspase
  • GSDMD
  • GSDME
  • apoptosis

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