A1902-1mg | Z-VAD-FMK [187389-52-2] Clinisciences

Background

Z-VAD-FMK, an inhibitor of ICE-like proteases, inhibits apoptosis in THP.1 cells induced by diverse stimuli¹ and Fas antigen-induced apoptosis in Jurkat T-cells². It inhibits apoptosis by blocking the activation of proCPP32 into its active form, rather than by preventing the proteolytic action of CPP32 directly.

Z- VAD-FMK inhibits the formation of large kilobasepair fragments of DNA induced by diverse stimuli. Z-VAD-FMK had little or no effect on STS-induced necrotic cell death suggesting that the ICE-like protease activity was not involved in necrosis³.

Z-VAD-FMK almost completely inhibited the formation of large kilobasepair induced by all four stimuli. Similarly Z-VAD-FMK almost completely inhibited the enhanced formation of large kilobasepair fragments induced by thapsigargin or cycloheximide in the presence of TLCK, in good agreement with its ability to inhibit apoptosis induced by these treatments. These stimuli also induced internucleosomal cleavage of DNA, which was inhibited by Z-VAD-FMK. These results suggested that an ICE-like protease(s) acts at a stage prior to the formation of large kilobasepair fragments of DNA³.

References:
1. Darmon, A.J., Ehrman, N., Caputo, A., Fujinaga, J. and Bleackley, R.C. (1994) J. Biol. Chem. 269, 32043-32046.
2. Chow, S. C., Weis M., Kass, G. E. N., Holmstrom, T. H., Eriksson, J. E. and Orrenius S. (1995) FEBS Lett. 364, 134±138
3. H. Zhu et al./FEBS Letters 374 (1995) 303-308

Product Citation

1. Yuan-Li Ai, Wei-Jia Wang, et al. "Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P." Cell Res. 2023 Jul 17. PMID: 37460805
2. Yaoyao Bian, Mei Xue, et al. "Cinobufagin induces acute promyelocytic leukaemia cell apoptosis and PML-RARA degradation in a caspase-dependent manner by inhibiting the β-catenin signalling pathway." Pharm Biol. 2022 Dec;60(1):1801-1811. PMID: 36121296
3. Noe´ mie Alphonse, Joseph J. Wanford, et al. "A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling." Cell. 2022 Jun 23;185(13):2354-2369.e17. PMID: 35568036
4. Jing Zhang, Christina Trojel-Hansen, et al. "Necrocide 1 Mediates a Non-Apoptotic Necrotic Cell Death and Immunogenic Response in Human Cancer Cells." Research Square.
5. Magdalena Delgado, Randall R. Rainwater, et al. "Primary acute lymphoblastic leukemia cells are susceptible to microtubule depolymerization in G1 and M phases through distinct cell death pathways." J Biol Chem. 2022 Jun;298(6):101939. PMID: 35436470
6. Tsolere Arakelian, Koen Oosterhuis, et al. "Pyroptosis-inducing active caspase-1 as a genetic adjuvant in anti-cancer DNA vaccination." Vaccine. 2022 Mar 18;40(13):2087-2098. PMID: 35177300
7. Yue Yang, yuanyuan Lu, et al. "Identification of A New Kind of Phenazine Compounds Attenuating The Stemness of Breast Cancer Cells Through Triggering Ferroptosis." Research Square. March 1st, 2021.
8. Jingchun Du, Yougui Xiang, et al. "RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis." Nat Commun. 2021 Dec 3;12(1):7067. PMID: 34862394
9. Xinxin Ren, Xiang Wang, et al. "Significance of TEAD Family in Diagnosis, Prognosis and Immune Response for Ovarian Serous Carcinoma." Int J Gen Med. 2021 Oct 27;14:7133-7143. PMID: 34737608
10. Ellie Esfandiari Nazzaro, Fahad Y Sabei, et al. "Discovery and Validation of a Compound to Target Ewing's Sarcoma." Pharmaceutics. 2021 Sep 24;13(10):1553. PMID: 34683845
11. Davide Pradella, Gianluca Deflorian, et al. "A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis." Nat Commun. 2021 Aug 11;12(1):4872. PMID: 34381052
12. Du Yu, Yundi Zhao, et al. "C19orf66 Inhibits Japanese Encephalitis Virus Replication by Targeting -1 PRF and the NS3 Protein." Virol Sin. 2021 Dec;36(6):1443-1455. PMID: 34309824
13. Chunhua Shu, Rui Wang, et al. "The "Dextran-Magnetic Layered Double Hydroxide-Fluorouracil" Drug Delivery System Exerts Its Anti-tumor Effect by Inducing Lysosomal Membrane Permeability in the Process of Cell Death." Biol Pharm Bull. 2021 Oct 1;44(10):1473-1483. PMID: 34305072
14. Qionghui Zhan, Jaepyo Jeon, et al. "CAMK2/CaMKII activates MLKL in short-term starvation to facilitate autophagic flux." Autophagy. 2022 Apr;18(4):726-744. PMID: 34282994
15. Indra Sarabia, Camille L Novis, et al. "Activation of the Anti-Oxidative Stress Response Reactivates Latent HIV-1 Through the Mitochondrial Antiviral Signaling Protein Isoform MiniMAVS." Front Immunol. 2021 Jun 14;12:682182. PMID: 34194436
16. Alicja Urbaniak, Megan R Reed, et al. "Single and double modified salinomycin analogs target stem-like cells in 2D and 3D breast cancer models." Biomed Pharmacother. 2021 Sep;141:111815. PMID: 34130123
17. Chi Yan, Nabil Saleh, et al. "Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade." Mol Cancer. 2021 Jun 6;20(1):85. PMID: 34092233
18. Jia-yuan Zhang, Bo Zhou, et al. "The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8." Cell Res. 2021 Sep;31(9):980-997. PMID: 34012073
19. Chueh-Yu Lin, Minh Tam Ly, et al. "Tanshinone IIA Shows Higher Antiproliferative Activities than Sinapic Acid in 4 Cancer Cell Lines and Simultaneously Induces Apoptosis and Necroptosis in Human Lung Cancer A549 Cells." Natural Product Communications Volume 16(10): 1–9
20. Tae-Yeon Kim, Ju-Hui Kang, et al. "Down-regulation of pro-necroptotic molecules blunts necroptosis during myogenesis." Biochem Biophys Res Commun. 2021 Jun 11;557:33-39. PMID: 33862457
21. Chu-di Zhang, Yi-Long Wang, et al. "A recombinant Chinese measles virus vaccine strain rMV-Hu191 inhibits human colorectal cancer growth through inducing autophagy and apoptosis regulating by PI3K/AKT pathway." Transl Oncol. 2021 Jul;14(7):101091. PMID: 33848808
22. Chunhua Rui, Shen-nan Shi, et al. "The multitargeted kinase inhibitor KW-2449 ameliorates cisplatin-induced nephrotoxicity by targeting RIPK1-mediated necroptosis." Biochem Pharmacol. 2021 Jun;188:114542. PMID: 33819469
23. Yanxiang Hu, Jing Wen, et al. "Precision control of mTORC1 is crucial for the maintenance and IL-13 responsiveness of alveolar macrophages."Int Immunopharmacol. 2021 Mar 17;95:107552. PMID: 33743315
24. Binghua Liu, Weiyan Wang, et al. "Sodium iodate induces ferroptosis in human retinal pigment epithelium ARPE-19 cells." Cell Death Dis. 2021 Mar 3;12(3):230. PMID: 33658488
25. Zhuo Sun, Yidan Cao, et al. "Antiangiogenic effect of arsenic trioxide in HUVECs by FoxO3a‐regulated autophagy." J Biochem Mol Toxicol. 2021 Feb 16;e22728. PMID: 33592126
26. Tanmoy Mondal, Gururaj N Shivange, et al. "Unexpected PD‐L1 immune evasion mechanism in TNBC, ovarian, and other solid tumors by DR5 agonist antibodies." EMBO Mol Med. 2021 Mar 5;13(3):e12716. PMID: 33587338
27. Xiaoli Liu, Yan Gu, et al. "Honokiol induces paraptosis-like cell death of acute promyelocytic leukemia via mTOR & MAPK signaling pathways activation." Apoptosis. 2021 Apr;26(3-4):195-208. PMID: 33550458
28. Zeinab Hosseini, Michael Marinello, et al. "Resolvin D1 Enhances Necroptotic Cell Clearance Through Promoting Macrophage Fatty Acid Oxidation and Oxidative Phosphorylation." Arterioscler Thromb Vasc Biol. 2021 Mar;41(3):1062-1075. PMID: 33472399
29. Zhijun Liu, Himani Nailwal, et al. "A class of viral inducer of degradation of the necroptosis adaptor RIPK3 regulates virus-induced inflammation." Immunity. 2021 Feb 9;54(2):247-258.e7. PMID: 33444549
30. Qi Wang, Yaxun Guo, et al. "RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA." Exp Cell Res. 2021 Feb 1;399(1):112453. PMID: 33358859
31. Zs´ofia Varga, Evelin R´acz, et al. "Cytotoxic activity of human dendritic cells induces RIPK1-dependent cell death." Immunobiology. 2020 Nov 23;226(1):152032. PMID: 33316542
32. Qin Hao, Suman Kundu, et al. "Enhanced RIPK3 kinase activity-dependent lytic cell death in M1 but not M2 macrophages." Mol Immunol. 2021 Jan;129:86-93. PMID: 33221042
33. Claire Reynolds-Peterson, Dylan J Ehrbar, et al. "Sensitization of Airway Epithelial Cells to Toxin-Induced Death by TNF Superfamily Cytokines." Methods Mol Biol. 2021;2248:19-42. PMID: 33185865
34. Runqing Geng, Yuanyuan Ren, et al. "Titanium Dioxide Nanoparticles Induced HeLa Cell Necrosis under UVA Radiation through the ROS-mPTP Pathway." Nanomaterials (Basel). 2020 Oct 15;10(10):E2029. PMID: 33076304
35. Smith HG, Jamal K, et al. "RIPK1-mediated immunogenic cell death promotes anti-tumour immunity against soft-tissue sarcoma." EMBO Mol Med. 2020;12(6):e10979. PMID: 32419365
36. Jessica H. Byerly, Elisa R. Port, et al. "PRKCQ inhibition enhances chemosensitivity of triple-negative breast cancer by regulating Bim." Breast Cancer Res. 2020 Jun 29;22(1):72. PMID: 32600444
37. Chen Z, Xu G, et al. "Lobaplatin induces pyroptosis through regulating cIAP1/2, Ripoptosome and ROS in nasopharyngeal carcinoma." Biochem Pharmacol. 2020;177:114023. PMID: 32413426
38. Dasari S, Bakthavachalam V, et al. "Neferine, an alkaloid from lotus seed embryo targets HeLa and SiHa cervical cancer cells via pro-oxidant anticancer mechanism." Phytother Res. 2020;10.1002/ptr.6687. PMID: 32364634
39. Panina SB, Pei J, et al. "Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy." Front Oncol. 2020;10:435. Published 2020 Apr 3. PMID: 32318340
40. Sadh S, Hajjar S, et al. "Coating M-CSF on plastic surface results in the generation of increased numbers of macrophages in vitro." J Immunol Methods. 2020;481-482:112788. PMID: 32304707
41. Kai J, Yang X, et al. "Oroxylin a promotes PGC-1α/Mfn2 signaling to attenuate hepatocyte pyroptosis via blocking mitochondrial ROS in alcoholic liver disease." Free Radic Biol Med. 2020;153:89-102. PMID: 32289481
42. Xia Qin, Longmiao Hu, et al. "The Bcr-Abl inhibitor GNF-7 inhibits necroptosis and ameliorates acute kidney injury by targeting RIPK1 and RIPK3 kinases." Biochem Pharmacol. 2020 Jul;177:113947. PMID: 32247850
43. El-Kadiry AE, Abusarah J, et al. "A Novel Sulfonyl-Based Small Molecule Exhibiting Anti-cancer Properties." Front Pharmacol. 2020;11:237. Published 2020 Mar 12. PMID: 32231565
44. Rasheed A, Robichaud S, et al. "Loss of MLKL (Mixed Lineage Kinase Domain-Like Protein) Decreases Necrotic Core but Increases Macrophage Lipid Accumulation in Atherosclerosis." Arterioscler Thromb Vasc Biol. 2020;40(5):1155-1167. PMID: 32212851
45. Kai Wang, Ruei-Zeng Lin, et al. "Robust differentiation of human pluripotent stem cells into endothelial cells via temporal modulation of ETV2 with modified mRNA." bioRxiv. March 5, 2020.
46. Su S, Dai H, et al. "Ethylene negatively mediates self-incompatibility response in Brassica rapa." Biochem Biophys Res Commun. 2020;S0006-291X(20)30409-5. PMID: 32115144
47. Ariana A, Alturki NA, et al. "Tristetraprolin regulates necroptosis during tonic Toll-like receptor 4 (TLR4) signaling in murine macrophages." J Biol Chem. 2020;jbc.RA119.011633. PMID: 32094226
48. Zhao M, Duan X, et al. "A Novel Role for PX, a Structural Protein of Fowl Adenovirus Serotype 4 (FAdV4), as an Apoptosis-Inducer in Leghorn Male Hepatocellular Cell." Cell. Viruses. 2020;12(2):E228. Published 2020 Feb 18. PMID: 32085479
49. Sun Y, Wang L, et al. "Phenols fragment of Veronica ciliata Fisch. ameliorate free radical-induced nonalcoholic fatty liver disease by mediating PI3K/Akt signaling pathway." J Ethnopharmacol. 2020;253:112579. PMID: 31978521
50. Otahal A, Aydemir D, et al. "Delineation of cell death mechanisms induced by synergistic effects of statins and erlotinib in non-small cell lung cancer cell (NSCLC) lines." Sci Rep. 2020;10(1):959. Published 2020 Jan 22. PMID: 31969600
51. Hanna-Addams S, Liu S, et al. "CK1α, CK1δ, and CK1ε are necrosome components which phosphorylate serine 227 of human RIPK3 to activate necroptosis." Proc Natl Acad Sci U S A. 2020;117(4):1962–1970. PMID: 31932442
52. Almacellas-Rabaiget O, Monaco P, et al. "LOXL2 promotes oncogenic progression in alveolar rhabdomyosarcoma independently of its catalytic activity." Cancer Lett. 2020;474:1–14. PMID: 31911079
53. Norah Abdullah Alturki. "Necrosome Activation and Degradation in Macrophages." Ottawa, Canada, 2020.
54. Urrutia G, Salmonson A, et al. "Combined Targeting of G9a and Checkpoint kinase 1 Synergistically Inhibits Pancreatic Cancer Cell Growth by Replication Fork Collapse." Mol Cancer Res. 2019 Dec 10. pii: molcanres.0490.2019. PMID: 31822519
55. Wang H, Liu C, et al. "Inhibition of LONP1 protects against erastin-induced ferroptosis in Pancreatic ductal adenocarcinoma PANC1 cells." Biochem Biophys Res Commun. 2019 Dec 7. pii:S0006-291X(19)32315-0. PMID: 31822343
56. Yang Y, Wei F, et al. "Manganese modifies Neurotrophin-3 (NT3) and its tropomyosin receptor kinase C (TrkC) in the cortex: Implications for manganese-induced neurotoxicity." Food Chem Toxicol. 2020;135:110925. PMID: 31676349
57. Agabiti SS, Li J, et al. "Regulation of the Notch-ATM-abl axis by geranylgeranyl diphosphate synthase inhibition." Cell Death Dis. 2019 Sep 30;10(10):733. PMID: 31570763
58. Gelles JD, Mohammed JN, et al. "Single-Cell and Population-Level Analyses Using Real-Time Kinetic Labeling Couples Proliferation and Cell Death Mechanisms." Dev Cell. 2019 Sep 25. pii: S1534-5807(19)30699-9. PMID: 31564612
59. Flaherty RA, Magel M, et al. "Modulation of death and inflammatory signaling in decidual stromal cells following exposure to Group B Streptococcus." Infect Immun. 2019 Sep 23. pii: IAI.00729-19. PMID: 31548323
60. Adil Rasheed, Sabrina Robichaud, et al. "Loss of MLKL Decreases Necrotic Core but Increases Macrophage Lipid Accumulation In Atherosclerosis." bioRxiv. 2019 August 28.
61. Mohammed Mohasin, Katharin Balbirnie-Cumming, et al. "Macrophages utilize mitochondrial fission to enhance mROS production during responses to Streptococcus pneumoniae." bioRxiv. 2019 August 02.
62. " Panina SB, Baran N, et al. "A mechanism for increased sensitivity of acute myeloid leukemia to mitotoxic drugs." Cell Death Dis. 2019 Aug 13;10(8):617. PMID: 31409768
63. Wang Z, Chen J, et al. "cGAS/STING axis mediates a topoisomerase II inhibitor-induced tumor immunogenicity." J Clin Invest. 2019 Aug 13;130:4850-4862. PMID: 31408442
64. McComb S, Chan PK, et al. "Efficient apoptosis requires feedback amplification of upstream apoptotic signals by effector caspase-3 or -7." Sci Adv. 2019 Jul 31;5(7):eaau9433. PMID: 31392262
65. Hodges AL, Kempen CG, et al. "TNF Family Cytokines Induce Distinct Cell Death Modalities in the A549 Human Lung Epithelial Cell Line when Administered in Combination with Ricin Toxin." Toxins (Basel). 2019 Aug 1;11(8). pii: E450. PMID: 31374990
66. Li J, Shi W, et al. "Activation of DR3 signaling causes loss of ILC3s and exacerbates intestinal inflammation." Nat Commun. 2019 Jul 29;10(1):3371. PMID: 31358760
67. JeongeunKima, HuijeongAhna, et al. "Obovatol inhibits NLRP3, AIM2, and non-canonical inflammasome activation." Phytomedicine. Available online 4 July 2019, 153019.
68. Gerlach BD, Marinello M, et al. "Resolvin D1 promotes the targeting and clearance of necroptotic cells." Cell Death Differ. 2020;27(2):525–539. PMID: 31222041
69. Yue W, Verhoeven C, et al. "Pro-Apoptotic Effects of Estetrol on Long-Term Estrogen-Deprived Breast Cancer Cells and at Low Doses on Hormone-Sensitive Cells." Breast Cancer (Auckl). 2019 May 15;13:1178223419844198. PMID: 31205415
70. Patel S, Webster JD, et al. "RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases." Cell Death Differ. 2019 May 17. PMID: 31101885
71. Jung H, Leal-Ekman JS, et al. "Atg14 protects the intestinal epithelium from TNF-triggered villus atrophy." Autophagy. 2019 Mar 20:1-12. PMID: 30894050
72. Podder B, Guttà C, et al. "TAK1 suppresses RIPK1-dependent cell death and is associated with disease progression in melanoma." Cell Death Differ. 2019 Mar 8. PMID: 30850732
73. Rello-Varona S, Fuentes-Guirado M, et al. "Bcl-x(L) inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas." Sci Rep. 2019 Mar 7;9(1):3816. PMID: 30846724
74. Yu XH, Hong XQ, et al. "Fluorinated bisbenzimidazoles: a new class of drug-like anion transporters with chloride-mediated, cell apoptosis-inducing activity." Org Biomol Chem. 2019 Feb 6;17(6):1558-1571. PMID: 30694281
75. Yang L, Joseph S, et al. "TAK1 regulates endothelial cell necroptosis and tumor metastasis." Cell Death Differ. 2019 Jan 25. PMID: 30683914
76. Rossi A, Pakhomova ON, et al. "Mechanisms and immunogenicity of nsPEF-induced cell death in B16F10 melanoma tumors." Sci Rep. 2019 Jan 23;9(1):431. PMID: 30674926
77. Hua S, Ma M, et al. "Glycyrrhizin attenuates hepatic ischemia-reperfusion injury by suppressing HMGB1-dependent GSDMD-mediated kupffer cells pyroptosis." Int Immunopharmacol. 2019 Mar;68:145-155. PMID: 30634142
78. Yuan Z, Zhang H, et al. "A new perspective of triptolide-associated hepatotoxicity: Liver hypersensitivity upon LPS stimulation." Toxicology. 2019 Feb 15;414:45-56. PMID: 30633930
79. YU HUANG. "STUDY OF REGULATED CELL DEATH IN TWO SYSTEMS: PD-1 IN NATURAL KILLER CELLS AND RIP3 IN NEURONS."The University of Texas. 2018.
80. Olga Almacellas Rabaiget."Caracterització funcional de LOXL2 en el rabdomiosarcoma alveolar."University of Barcelona.2018.
81. Liccardi G, Ramos Garcia L, et al. "RIPK1 and Caspase-8 Ensure Chromosome Stability Independently of Their Role in Cell Death and Inflammation." Mol Cell. 2018 Dec 28. pii: S1097-2765(18)30980-8. PMID: 30598363
82. LeBlanc L, Lee BK, et al. "Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation." Elife. 2018 Dec 18;7. pii: e40167. PMID: 30561326
83. In EJ, Lee Y, et al. "Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis." Molecules.2018 Nov 5;23(11). pii: E2884. PMID: 30400632
84. Yazhong Ge, Qing Gao, et al . "Su Yang Decoction induces human colon carcinoma cell apoptosis by activating caspases." Oncology letters.October 26, 2018.
85. Wang Y, Li Y, et al. "The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation." FASEB J. 2018 Sep 25:fj201800343R. PMID: 30252535
86. Ahn H, Kim J, et al. "Mercury and arsenic attenuate canonical and non-canonical NLRP3 inflammasome activation." Sci Rep. 2018 Sep 12;8(1):13659. PMID: 30209319
87. Santi Rello-Varona, Miriam Fuentes-Guirado, et al. "Bcl-xL inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas." bioRxiv. 2018 August 27.
88. Michael Abrams."Self-repair and Sleep in Jellyfish." California Institute of Technology.2018.
89. Rathkey JK, Zhao J, et al. "Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis." Sci Immunol. 2018 Aug 24;3(26). pii: eaat2738. PMID: 30143556
90. Liu TC, Kern JT, et al. "Interaction between smoking and ATG16L1T300A triggers Paneth cell defects in Crohn's disease."J Clin Invest. 2018 Aug 23. pii: 120453. PMID: 30137026
91. Rodriguez DA, Green DR. "Generation and Use of Chimeric RIP Kinase Molecules to Study Necroptosis." Methods Mol Biol. 2018;1857:71-83. PMID: 30136231
92. Alexander William David Binks B.Sc. "The role of immunogenic cell death in oncolytic herpes simplex virus-1 infection of cancer cells." University of Glasgow.2018.
93. Saleh D, Degterev A. "Chemical Library Screens to Identify Pharmacological Modulators of Necroptosis." Methods Mol Biol. 2018;1857:19-33. PMID: 30136227
94. Zhang QQ, Huang WQ, et al. "Metabolomics Reveals the Efficacy of Caspase Inhibition for Saikosaponin D-Induced Hepatotoxicity." Front Pharmacol. 2018 Jul 6;9:732. PMID: 30034340
95. Rijal D, Ariana A, et al. "Differentiated Macrophages Acquire a Pro-Inflammatory and Cell Death-Resistant Phenotype Due to Increasing XIAP and P38-mediated inhibition of RipK1." J Biol Chem. 2018 Jun 13. pii:jbc.RA118.003614. PMID: 29899110
96. Alturki NA, McComb S, et al. "Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis." Cell Death Dis. 2018 May 22;9(6):592. PMID: 29789521
97. Qianqian Zhang,Wanqiu Huang, et al. "Saikosaponins with similar structures but different mechanisms lead to combined hepatotoxicity" arXiv preprint. 14 May 2018.
98. Sarhan J, Liu BC, et al. "Constitutive interferon signaling maintains critical threshold of MLKL expression to license necroptosis." Cell Death Differ. 2018 May 21. PMID: 29786074
99. Sun T, Zhu T, et al. "Effects of Recombinant Circularly Permuted Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) (Recombinant Mutant Human TRAIL) in Combination with 5-Fluorouracil in Human Colorectal Cancer Cell Lines HCT116 and SW480." Med Sci Monit. 2018 Apr 26;24:2550-2561. PMID: 29695684
100. Gao X, Zheng Y, et al."Maduramicin induces apoptosis in chicken myocardial cells via intrinsic and extrinsic pathways." Toxicol In Vitro. 2018 Mar 23;50:190-200. PMID: 29580986
101. Wang JN, Zhang ZR, et al. "Acetyl-macrocalin B, an ent-kaurane diterpenoid, initiates apoptosis through the ROS-p38-caspase 9-dependent pathway and induces G2/M phase arrest via the Chk1/2-Cdc25C-Cdc2/cyclin B axis in non-small cell lung cancer." Cancer Biol Ther. 2018 Jul 3;19(7):609-621. PMID: 29565730
102. Wan X, Serrill JD, et al."ATG5 Promotes Death Signaling in Response to the Cyclic Depsipeptides Coibamide A and Apratoxin A." Mar Drugs. 2018 Mar 1;16(3). pii: E77. PMID: 29494533
103. Annibaldi A, Wicky John S, et al. "Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2." Mol Cell. 2018 Feb 15;69(4):566-580.e5. PMID: 29452637
104. Dos Santos AA, López-Granero C, et al."Oxidative stress, caspase-3 activation and cleavage of ROCK-1 play an essential role in MeHg-induced cell death in primary astroglial cells." Food Chem Toxicol.2018 Mar;113:328-336. PMID: 29428217
105. Lee YR, Chen SH, et al. "In Vitro Antitumor Activity of Aloperine on Human Thyroid Cancer Cells through Caspase-Dependent Apoptosis." Int J Mol Sci. 2018 Jan 21;19(1). pii: E312. PMID: 29361731
106. Lv DW, Zhang K, et al. "Interferon regulatory factor 8 regulates caspase-1 expression to facilitate Epstein-Barr virus reactivation in response to B cell receptor stimulation and chemical induction." PLoS Pathog. 2018 Jan 22;14(1):e1006868. PMID: 29357389
107. Wang J, Zhang Z, et al. "Rabdocoestin B exhibits antitumor activity by inducing G2/M phase arrest and apoptosis in esophageal squamous cell carcinoma." Cancer Chemother Pharmacol. 2018 Mar;81(3):469-481. PMID: 29308536
108. Hancz D, Szabo A, et al. "Flagellin increases death receptor-mediated cell death in a RIP1-dependent manner." Immunol Lett. 2017 Nov 23;193:42-50. PMID: 29175315
109. Kondratskyi A, Kondratska K, et al. "Ferroquine, the next generation antimalarial drug, has antitumor activity." Sci Rep. 2017 Nov 21;7(1):15896. PMID: 29162859
110. Matsuzawa-Ishimoto Y, Shono Y, et al. "Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium." J Exp Med. 2017 Dec 4;214(12):3687-3705. PMID: 29089374
111. Hao F, Cubero FJ, et al."Inhibition of Caspase-8 does not protect from alcohol-induced liver apoptosis but alleviates alcoholic hepatic steatosis in mice." Cell Death Dis. 2017 Oct 26;8(10):e3152. PMID: 29072704
112. Heather Koehlera, Samantha Cotsmirea, et al."Inhibition of DAI-dependent necroptosis by the Z-DNA binding domain of the vaccinia virus innate immune evasion protein, E3." Proc Natl Acad Sci U S A. 2017.August 31.
113. Wang J, He H, et al."Uncoupling effect of F16 is responsible for its mitochondrial toxicity and anti-cancer activity." Toxicol Sci. 2017 Oct 23. PMID: 29069523
114. Kleino A, Ramia NF, et al. "Peptidoglycan-Sensing Receptors Trigger the Formation of Functional Amyloids of the Adaptor Protein Imd to Initiate Drosophila NF-κB Signaling." Immunity. 2017 Oct 17;47(4):635-647.e6. PMID: 29045898
115. Circu M, Cardelli J, et al. "Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells." PLoS One. 2017 Sep 25;12 (9):e0184922. PMID: 28945807
116. Oltean A, Taber LA. "Apoptosis Generates Mechanical Forces that Close the Lens Vesicle in the Chick Embryo." Phys Biol. 2017 Sep 15. PMID: 28914615
117. Reynoso E, Liu H, et al. "Thioredoxin-1 actively maintains the pseudokinase MLKL in a reduced state to suppress disulfide bond-dependent MLKL polymer formation and necroptosis." J Biol Chem. 2017 Sep 6.pii: jbc.M117.799353. PMID: 28878015
118. Dikchha Rijal. "Cell death signaling complexes during macrophage differentiation." University of Ottawa,2017
119. Gong YN, Guy C, et al. "Biological events and molecular signaling following MLKL activation during necroptosis." Cell Cycle. 2017 Oct 2;16(19):1748-1760. PMID: 28854080
120. Liu S, Liu H, et al. "MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis." Proc Natl Acad Sci U S A. 2017 Aug 21. PMID: 28827318
121. Yosef R, Pilpel N, et al. "p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling." EMBO J. 2017 Jun 12. pii: e201695553. PMID: 28607003
122. Jaco I, Annibaldi A, et al. "MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death." Mol Cell. 2017 Jun 1;66(5):698-710.e5. PMID: 28506461
123. Ma Y, Walsh MJ, et al. "CRISPR/Cas9 Screens Reveal Epstein-Barr Virus-Transformed B Cell Host Dependency Factors." Cell Host Microbe.2017 May 10;21(5):580-591.e7. PMID: 28494239
124. Boyd-Tressler AM, Lane GS, et al. "Up-regulated Ectonucleotidases in Fas-Associated Death Domain Protein- and Receptor-Interacting Protein Kinase 1-Deficient Jurkat Leukemia Cells Counteract Extracellular ATP/AMP Accumulation via Pannexin-1 Channels during Chemotherapeutic Drug-Induced Apoptosis." Mol Pharmacol. 2017 Jul;92(1):30-47. PMID: 28461585
125. Saleh D, Najjar M, et al. "Kinase Activities of RIPK1 and RIPK3 Can Direct IFN-β Synthesis Induced by Lipopolysaccharide." J Immunol. 2017 Jun 1;198(11):4435-4447. PMID: 28461567
126. Chirieleison SM, Marsh RA, et al."Nucleotide-binding oligomerization domain (NOD) signaling defects and cell death susceptibility cannot be uncoupled in X-linked inhibitor of apoptosis (XIAP)-driven inflammatory disease." J Biol Chem. 2017 Apr 12. pii:jbc.M117.781500. PMID: 28404814
127. Gong YN, Guy C, et al. "ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences." Cell. 2017 Apr 6;169(2):286-300.e16. PMID: 28388412
128. Ros U, Pe?a-Blanco A, et al. "Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium." Cell Rep. 2017 Apr 4;19(1):175-187. PMID: 28380356
129. Ardeshir Ariana,Faculty of Medicine, et al, "Dissection of TLR4-induced necroptosis using specific inhibitors of endocytosis and p38 MAPK." University of Ottawa. 2017.
130. Agabiti SS, Li J, et al. "Geranylgeranyl diphosphate synthase inhibition induces apoptosis that is dependent upon GGPP depletion, ERK phosphorylation and caspase activation." Cell Death Dis. 2017 Mar 16;8(3):e2678. PMID: 28300835
131. Faculty of Medicine University of Ottawa,et al. "FoxO3a signaling promotes the inflammatory response during Salmonella Typhimurium infection."University of Ottawa, 2017.
132. Weigert, Melanie. "Investigating the role of programmed necrosis in oncolytic adenovirus-induced death." university of glasgow.2017 May 01.
133. Mohammed A. Alamri. "Syntheses and Evaluations of Bicycloheptylamines and Cyclohexylamines as Sigma-2 Receptor Ligands and Their Potential as Anticancer Agents." University of the Sciences in Philadelphia.2017.
134. Iurlaro R, Püschel F, et al. "Glucose Deprivation Induces ATF4-Mediated Apoptosis through TRAIL Death Receptors." Mol Cell Biol. 2017 May 2;37(10). pii: e00479-16. PMID: 28242652
135. Cirka HA, Uribe J, et al. "Reproducible in vitro model for dystrophic calcification of cardiac valvular interstitial cells: insights into the mechanisms of calcific aortic valvular disease." Lab Chip. 2017 Feb 28;17(5):814-829. PMID: 28128382
136. Rogers C, Fernandes-Alnemri T, et al."Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death." Nat Commun. 2017 Jan 3;8:14128. PMID: 28045099
137. Lordén G, Sanjuán-García I, et al. "Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation." J Exp Med. 2017 Feb;214(2):511-528. PMID: 28031477
138. Gelles JD, Edward Chipuk J. "Robust high-throughput kinetic analysis of apoptosis with real-time high-content live-cell imaging. Cell Death Dis." 2016 Dec 1;7(12):e2493. PMID: 27906190
139. Vylkova S, Lorenz MC. "Phagosomal Neutralization by the Fungal Pathogen Candida albicans Induces Macrophage Pyroptosis." Infect Immun. 2017 Jan 26;85(2). pii:e00832-16. PMID: 27872238
140. Lin CY, Chang TW, et al. "Simultaneous induction of apoptosis and necroptosis by Tanshinone IIA in human hepatocellular carcinoma HepG2 cells." Cell Death Discov. 2016 Oct 3;2:16065. PMID: 27752362
141. Li J, Falcone ER, et al. "Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis." Pharmacol Res. 2016 Sep 20;113(Pt A):438-448. PMID: 27663262
142. Rozic G, Paukov L, et al. "The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo." Oncotarget. 2016 Sep 20;7(38):62572-62584. PMID: 27613836
143. Li Y, Li A, et al. "MiR-182-5p protects inner ear hair cells from cisplatin-induced apoptosis by inhibiting FOXO3a." Cell Death Dis. 2016 Sep 8;7(9):e2362. PMID: 27607577
144. Katey J. RAYNER, Terrence David RUDDY, et al. "IDENTIFICATION AND TREATMENT OF (52) U.S. Cl.VULNERABLE PLAQUES." US Patent App. 15 ,2016.
145. Peng Y, Miao H, et al. "ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2." Autophagy. 2016 Nov;12(11):2167-2182. PMID: 27559856
146. Karunakaran D, Geoffrion M, et al. "Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis." Sci Adv. 2016 Jul 22;2(7):e1600224. PMID: 27532042
147. Shi XJ, Yu B, et al. "Structurally novel steroidal spirooxindole by241 potently inhibits tumor growth mainly through ROS-mediated mechanisms." Sci Rep. 2016 Aug 16;6:31607. PMID: 27527552
148. Russo HM, Rathkey J, et al."Active Caspase-1 Induces Plasma Membrane Pores That Precede Pyroptotic Lysis and Are Blocked by Lanthanides." J Immunol. 2016 Aug 15;197(4):1353-67. PMID: 27385778
149. Yalon M, Tuval-Kochen L, et al. "Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations." PLoS One. 2016 May 19;11(5):e0155711. PMID: 27196668
150. McComb S, Aguadé-Gorgorió J, et al. "Activation of concurrent apoptosis and necroptosis by SMAC mimetics for the treatment of refractory and relapsed ALL." Sci Transl Med. 2016 May 18;8(339):339ra70. PMID: 27194728
151. Simon PS, Bardhan K, et al. "NF-κB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression." Oncotarget. 2016 Apr 26;7(17):23395-415. PMID: 27014915
152. Boyd Tressler, Andrea Michelle. "Mechanisms of Extracellular Nucleotide Accumulation During Regulated Cell Death in Tumor Cells."rave.ohiolink.edu,May 2016.
153. Hsieh Y Y, Chou C J, et al. "Repositioning of a cyclin-dependent kinase inhibitor GW8510 as a ribonucleotide reductase M2 inhibitor to treat human colorectal cancer[J]." Cell Death Discovery, 2016, 2.
154. Del Olmo I, López JA, et al. "Arabidopsis DNA polymerase ? recruits components of Polycomb repressor complex to mediate epigenetic gene silencing." Nucleic Acids Res. 2016 Jul 8;44(12):5597-614. PMID: 26980282
155. Zhao XM, Chen Z, et al. "Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis." Cell Death Dis. 2016 Feb 11;7:e2089. PMID: 26866270
156. Shah A, Vaidya NK, et al. "HIV-1 gp120 induces type-1 programmed cell death through ER stress employing IRE1α, JNK and AP-1 pathway." Sci Rep. 2016 Jan 7;6:18929. PMID: 26740125
157. Chan, Zou, et al. "Design, Synthesis and Biological Evaluation of 1‐Benzyl‐1H‐pyrazole Derivatives as Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors." Chemical biology & drug design (2015). PMID: 26577270
158. Duan, Wenwen, et al. "Protein C‐terminal enzymatic labeling identifies novel caspase cleavages during the apoptosis of multiple myeloma cells induced by kinase inhibition." Proteomics (2015). PMID: 26552366
159. Harris, Katharine G., and Carolyn B. Coyne. "Unc93b Induces Apoptotic Cell Death and Is Cleaved by Host and Enteroviral Proteases." PloS one 10.10 (2015): e0141383. PMID: 26509685
160. Tian, Chongchong, et al. "A novel dual EGFR/HER2 inhibitor KU004 induces cell cycle arrest and apoptosis in HER2-overexpressing cancer cells." Apoptosis 20.12 (2015): 1599-1612. PMID: 26437915
161. Hiller, Bradley E., Angela K. Berger, and Pranav Danthi. "Viral gene expression potentiates reovirus-induced necrosis." Virology 484 (2015): 386-394. PMID: 26226583
162. Fiesel, Fabienne C, et al. "(Patho‐) physiological relevance of PINK1‐dependent ubiquitin phosphorylation." EMBO reports (2015): e201540514. PMID: 26162776
163. Kang, Seokwon, et al. "Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3." Nature communications 6 (2015). PMID: 26104484
164. Antonopoulos, Christina, et al. "Caspase-8 as an Effector and Regulator of NLRP3 Inflammasome Signaling." Journal of Biological Chemistry (2015): jbc-M115. PMID: 26100631
165. Abrams, Michael J., et al. "Self-repairing symmetry in jellyfish through mechanically driven reorganization." Proceedings of the National Academy of Sciences (2015): 201502497. PMID: 26080418
166. Rodriguez, D. A., et al. "Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis." Cell Death & Differentiation (2015). PMID: 26024392
167. Xiong, J., et al. "Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting." Blood cancer journal 5.3 (2015): 287. PMID: 25768400
168. Rayavarapu R R, Heiden B, Pagani N, et al. "The Role of Multicellular Aggregation in the Survival of ErbB2-Positive Breast Cancer Cells during Extracellular Matrix-Detachment[J]". Journal of Biological Chemistry, 2015: jbc. M114. 612754. PMID: 25681438
169. Lu, Kang, et al. "The STAT3 inhibitor WP1066 reverses the resistance of chronic lymphocytic leukemia cells to histone deacetylase inhibitors induced by interleukin-6." Cancer Letters (2015). PMID: 25636517
170. Karmakar, Mausita, et al. "Neutrophil IL-1β Processing Induced by Pneumolysin Is Mediated by the NLRP3/ASC Inflammasome and Caspase-1 Activation and Is Dependent on K+ Efflux." The Journal of Immunology (2015): 1401624. PMID: 25609842
171. El Zaoui, Ikram, Francine Behar-Cohen, and Alicia Torriglia. "Glucocorticoids exert direct toxicity on microvasculature: Analysis of cell death mechanisms." Toxicological Sciences (2014): kfu243. PMID: 25447644
172. Boyd-Tressler, Andrea, et al. "Chemotherapeutic Drugs Induce ATP Release via Caspase-gated Pannexin-1 Channels and a Caspase/Pannexin-1-Independent Mechanism." Journal of Biological Chemistry (2014): jbc-M114. PMID: 25112874

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Chemical Properties

Storage	Store at -20°C
M.Wt	467.49
Cas No.	187389-52-2
Formula	C₂₂H₃₀FN₃O₇
Synonyms	Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone,Z-Val-Ala-Asp(OMe)-FMK
Solubility	≥23.37 mg/mL in DMSO; insoluble in EtOH; insoluble in H2O
Chemical Name	methyl (3S)-5-fluoro-3-[[(2S)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]-4-oxopentanoate
SDF	Download SDF
Canonical SMILES	CC(C)C(C(=O)NC(C)C(=O)NC(CC(=O)OC)C(=O)CF)NC(=O)OCC1=CC=CC=C1
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Kinase experiment [1]:
Preventing the processing of CPP32 to its active form	Z-VAD-FMK inhibits apoptosis by inhibiting the activation of CPP32, which presumably blocked the process by interfering directly with the processing of CPP32.
Cell experiment [2]:
Cell lines	Human CD4+ (~ 97%) and CD8+ T (~ 98%) cells
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37°C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
Reaction Conditions	24 h
Applications	Z-VAD-FMK dose-dependently inhibited T cell proliferation mediated through the co-stimulation with anti-CD3 and anti-CD28. Z-IETD-FMK was less effective at 25 and 50 μM, but inhibited T cell proliferation at the 100 μM concentration.
Animal experiment [3]:
Animal models	C57BL mice
Dosage form	1.25 mM, ear provocation
Applications	The right ear swelling degree, weight differences and thickness between two ears in the 1.25 mM Z-VAD-FMK group were significantly lower than those of the negative control (NC). The levels of INF-γ and IL-2 in the ear skin lesions, the mean intensity of BrdU in T lymphocytes, and the percent of activation markers-positive T lymphocytes were all lower than those of NC.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1]. Slee EA1, Zhu H, Chow SC et al. Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK) inhibits apoptosis by blocking the processing of CPP32. Biochem J. 1996 Apr 1;315 ( Pt 1):21-4. [2]. Lawrence CP1, Chow SC. Suppression of human T cell proliferation by the caspase inhibitors, z-VAD-FMK and z-IETD-FMK is independent of their caspase inhibition properties. Toxicol Appl Pharmacol. 2012 Nov 15;265(1):103-12. [3]. Li YY, Yan CL. Inhibition of elicitation of allergic contact dermatitis by topical use of Z-VAD-FMK, a broad caspase inhibitor: experiment in mice. Zhonghua Yi Xue Za Zhi. 2012 Jul 24;92(28):1992-6.

Biological Activity

Cell-permeable, irreversible pan-caspase inhibitor. Inhibits caspase processing and apoptosis induction in tumor cells in vitro (IC50 = 0.0015 - 5.8 mM). Active in vivo.
Targets	Caspase
IC50	0.0015 - 5.8 mM