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Apoptosis

As one of the cellular death mechanisms, apoptosis, also known as programmed cell death, can be defined as the process of a proper death of any cell under certain or necessary conditions. Apoptosis is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body.

Many biochemical events and a series of morphological changes occur at the early stage and increasingly continue till the end of apoptosis process. Morphological event cascade including cytoplasmic filament aggregation, nuclear condensation, cellular fragmentation, and plasma membrane blebbing finally results in the formation of apoptotic bodies. Several biochemical changes such as protein modifications/degradations, DNA and chromatin deteriorations, and synthesis of cell surface markers form morphological process during apoptosis.

Apoptosis can be stimulated by two different pathways: (1) intrinsic pathway (or mitochondria pathway) that mainly occurs via release of cytochrome c from the mitochondria and (2) extrinsic pathway when Fas death receptor is activated by a signal coming from the outside of the cell.

Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis.

Caspase family comprises conserved cysteine aspartic-specific proteases, and members of caspase family are considerably crucial in the regulation of apoptosis. There are 14 different caspases in mammals, and they are basically classified as the initiators including caspase-2, -8, -9, and -10; and the effectors including caspase-3, -6, -7, and -14; and also the cytokine activators including caspase-1, -4, -5, -11, -12, and -13. In vertebrates, caspase-dependent apoptosis occurs through two main interconnected pathways which are intrinsic and extrinsic pathways. The intrinsic or mitochondrial apoptosis pathway can be activated through various cellular stresses that lead to cytochrome c release from the mitochondria and the formation of the apoptosome, comprised of APAF1, cytochrome c, ATP, and caspase-9, resulting in the activation of caspase-9. Active caspase-9 then initiates apoptosis by cleaving and thereby activating executioner caspases. The extrinsic apoptosis pathway is activated through the binding of a ligand to a death receptor, which in turn leads, with the help of the adapter proteins (FADD/TRADD), to recruitment, dimerization, and activation of caspase-8 (or 10). Active caspase-8 (or 10) then either initiates apoptosis directly by cleaving and thereby activating executioner caspase (-3, -6, -7), or activates the intrinsic apoptotic pathway through cleavage of BID to induce efficient cell death. In a heat shock-induced death, caspase-2 induces apoptosis via cleavage of Bid.

Bcl-2 family members are divided into three subfamilies including (i) pro-survival subfamily members (Bcl-2, Bcl-xl, Bcl-W, MCL1, and BFL1/A1), (ii) BH3-only subfamily members (Bad, Bim, Noxa, and Puma9), and (iii) pro-apoptotic mediator subfamily members (Bax and Bak). Following activation of the intrinsic pathway by cellular stress, pro‑apoptotic BCL‑2 homology 3 (BH3)‑only proteins inhibit the anti‑apoptotic proteins Bcl‑2, Bcl-xl, Bcl‑W and MCL1. The subsequent activation and oligomerization of the Bak and Bax result in mitochondrial outer membrane permeabilization (MOMP). This results in the release of cytochrome c and SMAC from the mitochondria. Cytochrome c forms a complex with caspase-9 and APAF1, which leads to the activation of caspase-9. Caspase-9 then activates caspase-3 and caspase-7, resulting in cell death. Inhibition of this process by anti‑apoptotic Bcl‑2 proteins occurs via sequestration of pro‑apoptotic proteins through binding to their BH3 motifs.

One of the most important ways of triggering apoptosis is mediated through death receptors (DRs), which are classified in TNF superfamily. There exist six DRs: DR1 (also called TNFR1); DR2 (also called Fas); DR3, to which VEGI binds; DR4 and DR5, to which TRAIL binds; and DR6, no ligand has yet been identified that binds to DR6. The induction of apoptosis by TNF ligands is initiated by binding to their specific DRs, such as TNFα/TNFR1, FasL /Fas (CD95, DR2), TRAIL (Apo2L)/DR4 (TRAIL-R1) or DR5 (TRAIL-R2). When TNF-α binds to TNFR1, it recruits a protein called TNFR-associated death domain (TRADD) through its death domain (DD). TRADD then recruits a protein called Fas-associated protein with death domain (FADD), which then sequentially activates caspase-8 and caspase-3, and thus apoptosis. Alternatively, TNF-α can activate mitochondria to sequentially release ROS, cytochrome c, and Bax, leading to activation of caspase-9 and caspase-3 and thus apoptosis. Some of the miRNAs can inhibit apoptosis by targeting the death-receptor pathway including miR-21, miR-24, and miR-200c.

p53 has the ability to activate intrinsic and extrinsic pathways of apoptosis by inducing transcription of several proteins like Puma, Bid, Bax, TRAIL-R2, and CD95.

Some inhibitors of apoptosis proteins (IAPs) can inhibit apoptosis indirectly (such as cIAP1/BIRC2, cIAP2/BIRC3) or inhibit caspase directly, such as XIAP/BIRC4 (inhibits caspase-3, -7, -9), and Bruce/BIRC6 (inhibits caspase-3, -6, -7, -8, -9). 

Any alterations or abnormalities occurring in apoptotic processes contribute to development of human diseases and malignancies especially cancer.

 

References:

1.Yağmur Kiraz, Aysun Adan, Melis Kartal Yandim, et al. Major apoptotic mechanisms and genes involved in apoptosis[J]. Tumor Biology, 2016, 37(7):8471.

2.Aggarwal B B, Gupta S C, Kim J H. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey.[J]. Blood, 2012, 119(3):651.

3.Ashkenazi A, Fairbrother W J, Leverson J D, et al. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors[J]. Nature Reviews Drug Discovery, 2017.

4.McIlwain D R, Berger T, Mak T W. Caspase functions in cell death and disease[J]. Cold Spring Harbor perspectives in biology, 2013, 5(4): a008656.

5.Ola M S, Nawaz M, Ahsan H. Role of Bcl-2 family proteins and caspases in the regulation of apoptosis[J]. Molecular and cellular biochemistry, 2011, 351(1-2): 41-58.

Products for  Apoptosis

Research Area

  1. Cat.No. Product Name Information
  2. B6023 PD-1/PD-L1 inhibitor 2 PD-1/PD-L1 interaction inhibitor
  3. A3523 Kaempferol Apoptosis inducer;antioxidant;flavonoid
  4. A1902 Z-VAD-FMK Cell-permeable, irreversible pan-caspase inhibitor
  5. A9901 Caspase Inhibitor Set I Caspase Inhibitors
  6. A1901 Q-VD-OPh hydrate Top Seller Cell-permeable, irreversible pan-caspase inhibitor
  7. A1925 Caspase-3/7 Inhibitor I Top Seller Caspase-3/7 inhibitor
  8. A8955 Z-YVAD-FMK Caspase-1 inhibitor
  9. A1921 Z-DQMD-FMK Top Seller Caspase-3 inhibitor,cell-permeable
  10. A1922 Z-VDVAD-FMK Top Seller Caspase-2 inhibitor
  11. A1923 Z-VEID-FMK Top Seller Caspase-6 inhibitor
  12. A1920 Z-DEVD-FMK Top Seller Caspase-3 inhibitor
  13. A8238 VX-765 Caspase-1 inhibitor,potent and selective
  14. A8165 Q-VD(OMe)-OPh Top Seller Pan-caspase inhibitor
  15. A8177 PAC-1 Top Seller Procaspase-3 activator
  16. B3233 Z-LEHD-FMK Irreversible Caspase-9 inhibitor.
  17. B3232 Z-IETD-FMK Caspase-8 inhibitor
  18. A1930 Apoptosis Inhibitor Top Seller Associate with caspase-3 inhibition
  19. A1924 Z-WEHD-FMK Caspase 5 inhibitor,potent,cell-permeable and irreversible
  20. A1904 Boc-D-FMK Pan-caspase inhibitor
  21. A3424 Gambogic Acid Caspase activator and apoptosis inducer
  22. A8170 Z-FA-FMK Top Seller Cysteine proteases inhibitor
  23. A8321 Cisplatin Top Seller Inhibits DNA synthesis,chemotherapy drug
  24. A4016 Apoptosis Activator 2 Indoledione caspase activator, cell-permeable
  25. A4418 Ac-IEPD-AFC Recognition motif for serine protease granzyme B
  26. A4419 Ac-LEHD-AFC Fluorogenic caspase substrate
  27. A4416 AZ 10417808 Caspase-3 inhibitor,selective non-peptide
  28. A4417 Ivachtin Caspase-3 inhibitor
  29. A4420 PETCM Caspase-3 activator
  30. B4618 Emricasan potent irreversible pan-caspase inhibitor
  31. A4446 R18 14.3.3 proteins Antagonist
  32. A3327 Costunolide Apoptosis inducer
  33. B4782 Epibrassinolide Potential apoptosis inducer;steroidal plant growth stimulant
  34. A4234 TW-37 Top Seller Bcl-2 inhibitor, inhibits Bcl-2,Bcl-XL and Mcl-1
  35. C3528 Citrinin mycotoxin that induces apoptosis and blocks tubulin polymerization as well as mitotic spindle assembly
  36. C3296 MPI-0441138 inducer of apoptosis and growth inhibition
  37. B7760 CFM 4 Interferes with CARP-1 binding to APC-2
  38. A1984 Bendamustine HCl Cytostatic agent for non-Hodgkin lymphomas
  39. A8244 Cycloheximide Antibiotic,inhibiter of protein synthesis in eukaryotes
  40. A4453 NSC 687852 (b-AP15) 19S regulatory particle Inhibitor
  41. A8176 Apicidin Potent HDAC inhibitor
  42. N1719 Kaempferol Apoptosis inducer;antioxidant;flavonoid
  43. A4188 2-Methoxyestradiol (2-MeOE2) Apoptotic, antiproliferative and antiangiogenic agent
  44. A3218 BAM7 BAX activator,direct and selective
  45. A3237 Betulinic acid Anti-HIV and antitumor compound,pentacyclic triterpenoid
  46. A4452 Mitomycin C Inhibits DNA synthesis,antibiotic and antitumor agent
  47. A3118 3,3'-Diindolylmethane Anticancer and antineoplastic agent
  48. A3265 Brassinolide Plant growth regulator
  49. A3278 Capsaicin TRPV1 receptor agonist
  50. A3335 Curcumin Tyrosinase inhibitor
  51. A3583 Matrine Alkaloid found in Sophora plant
  52. A3746 R1530 Antiangiogenesis,mitosis-angiogenesis inhibitor (MAI)
  53. A3826 SMIP004 Apoptosis inducer
  54. A3886 Trabectedin Antitumour agent
  55. B4760 Raltegravir potassium salt HIV integrase inhibitor
  56. B1228 PM00104 Potent antimyeloma agent
  57. B3255 Meisoindigo Apoptosis inducer;potential agent for AML
  58. A4448 Actinomycin D RNA polymerase inhibitor
  59. A4447 2,3-DCPE hydrochloride Bcl-XL protein expression downregulator
  60. A4449 C 75 Fatty acid synthase (FAS) inhibitor
  61. A4450 CHM 1 Tubulin polymerization inhibitor
  62. A8188 Atractyloside Dipotassium Salt ANT inhibitor
  63. A4451 Deguelin Anticancer and antiviral agent
  64. A4454 Oncrasin 1 Proapoptotic agent
  65. A4457 Streptozocin Antibiotic and antitumor agent
  66. A4455 Piperlongumine Inducer of cell-death
  67. A4456 Plumbagin Anticancer agent
  68. A4484 PRIMA-1MET Top Seller Restore mutant p53 activity, induce BAX and PUMA
  69. A4459 Bax channel blocker Inhibitor of Bax-mediated mitochondrial cytochrome c release
  70. A4483 PRIMA-1 Top Seller BAX inhibitor
  71. A4460 Bax inhibitor peptide P5 Bax inhibitor
  72. A4461 Bax inhibitor peptide V5 Bax inhibitor
  73. A4462 Bax inhibitor peptide, negative control Peptide inhibit Bax translocation to mitochondria
  74. A3935 WEHI-539 Bcl-xL inhibitor,potent and selective
  75. B6094 BH3I-1 Bcl-2 or Bcl-XL inhibitor
  76. A8737 S63845 MCL1 inhibitor
  77. B6011 A-1210477 MCL-1 inhibitor
  78. B5978 BDA-366 Selective antagonist of BCL2 BH4 domain
  79. B5846 Radotinib(IY-5511) Bcr-Abl tyrosine kinase inhibitor
  80. B4902 (+)-Apogossypol inhibitor of Bcl-2 family proteins
  81. A8194 ABT-199 Bcl-2 inhibitor,potent and selective
  82. A8193 ABT-737 Top Seller Bcl-2 inhibitor
  83. A3007 ABT-263 (Navitoclax) Potent Bcl-2 family inhibitor, inhibits Bcl-2, Bcl-xL, and Bcl-w
  84. A9902 Bcl Family Set I Bcl family inhibitors
  85. B4901 Pyridoclax Mcl-1 inhibitor
  86. B4881 UMI-77 Mcl-1 inhibitor, novel
  87. A4194 Obatoclax mesylate (GX15-070) Potent Bcl-2 inhibitor
  88. A8168 HA14-1 Top Seller Bcl-2 inhibitor,potent and cell-permeable
  89. B1080 Marinopyrrole A Selective Mcl-1 inhibitor
  90. A4199 Sabutoclax pan-Bcl-2 inhibitor
  91. A4198 BM-1074 Bcl-2/Bcl-xL inhibitor,potent and selective
  92. A4200 Apogossypolone (ApoG2) Bcl-2 inhibitor,nonpeptidic small molecule
  93. A4463 BIM, Biotinylated Bim peptide fragment with a biotin moiety attached
  94. A4464 iMAC2 MAC inhibitor
  95. A4465 MIM1 Mcl-1 Inhibitor
  96. A4466 Muristerone A TRAIL- and hFasL-induced apoptosis inhibitor
  97. N2135 Gossypol PAF inhibitor;anti-fertility and anti-cancer
  98. A3196 AT-101 BH3-mimetic,gossypol enantiomer
  99. B4691 Mcl1-IN-1 Myeloid cell factor 1 inhibitor
  100. A8634 WEHI-539 hydrochloride Bcl-xL inhibitor,high affinity and selective
  101. B6163 A-1155463 BCL-XL inhibitor, potent and selective
  102. B6164 A-1331852 BCL-XL inhibitor, potent and selective
  103. A3847 SU5416 VEGF receptor inhibitor and AHR agonist
  104. A4237 Amuvatinib (MP-470, HPK 56) Top Seller Tyrosine kinase inhibitor
  105. A4116 Danusertib (PHA-739358) Top Seller Pan-aurora kinase inhibitor
  106. A4145 TG101209 Top Seller JAK2/3 inhibitor
  107. C4239 RPI-1 ATP-dependent RET kinase inhibitor
  108. C3080 AD57 (hydrochloride) polypharmacological cancer therapeutic that inhibits RET.
  109. A8236 Regorafenib Top Seller Inhibitor of VEGFR/PDGFR/FGFR/mutant kit/RET/Raf-1
  110. A3750 Regorafenib hydrochloride Tyrosine kinase inhibitor
  111. A3751 Regorafenib monohydrate Tyrosine kinase inhibitor
  112. A3891 Triptolide IL-2/MMP-3/MMP7/MMP19 inhibitor
  113. A4221 YM155 Survivin suppressant,apoptosis inhibitor
  114. A4219 Birinapant (TL32711) Potent XIAP/cIAP1 antagonist
  115. A3019 AT-406 (SM-406) IAP inhibitor
  116. A8815 SM-164 Anticancer agent
  117. A8235 Embelin XIAP inhibitor,cell-permeable
  118. A4224 GDC-0152 IAP antagonist,potent amd samll-molecule
  119. A3541 LCL161 Antagonist of IAPs inhibitor
  120. B4653 BV6 Selective inhibitor of IAP proteins
  121. N2285 Dimethylfraxetin Extracted from Fraxinus chinensis;Store the product in sealed, cool and dry condition.
  122. A3220 Bardoxolone Once-a-day treatment for CKD
  123. C3234 2-HBA indirect inducer of enzymes that catalyze detoxification reactions through the Keap1-Nrf2-ARE pathway.
  124. B1931 Dimethyl Fumarate nuclear factor (erythroid-derived)-like 2 (Nrf2) pathway activator
  125. B3577 CDDO-EA activator of Nrf2/ARE
  126. B3576 Omaveloxolone (RTA-408) Nrf2 activator
  127. A2005 Nutlin-3b MDM2/p53 inhibitor
  128. A4204 JNJ-26854165 (Serdemetan) Top Seller P53 activator, blocking Mdm2-p53 interaction
  129. A9903 p53/MDM2 Set I For inhibiting MDM2-p53 interaction
  130. A4202 RITA (NSC 652287) Mdm2-p53 interaction and p53 ubiquitination blocking
  131. B6058 (±)-Nutlin-3 MDM2 antagonist, potent and selective
  132. C4120 SP 141 Mdm2 inhibitor
  133. A3762 RG7112 MDM2 inhibitor, first clinical
  134. B4984 MI-773 (SAR405838) orally available MDM2 antagonist
  135. B4813 Pifithrin-β potent p53 inhibitor
  136. A3763 RG7388 MDM2 antagonist, oral, selective
  137. A3693 p53 and MDM2 proteins-interaction-inhibitor chiral P53 and MDM2 proteins-interaction-inhibitor
  138. A3694 p53 and MDM2 proteins-interaction-inhibitor racemic P53 and MDM2 proteins-interaction-inhibitor
  139. B4756 YH239-EE p53-MDM2 antagonist, potent
  140. A4209 NSC 207895 (XI-006) MDMX inhibitor,anti-cancer agent
  141. A4230 NSC 66811 MDM2 inhibitor
  142. A4228 Nutlin-3 Top Seller MDM2 antagonist,inhibits MDM2-p53 interaction
  143. A4206 Pifithrin-α (PFTα) p53 inhibitor
  144. C3846 p-nitro-Pifithrin-α inactivator of p53
  145. C3171 CBL0137 curaxin that activates p53 and inhibits NF-κB
  146. B6198 ReACp53 inhibit p53 amyloid formation
  147. B6190 NSC348884 nucleophosmin inhibitor
  148. B6045 NSC59984 Restores the p53 signaling pathway
  149. A8724 ONC201 activates p53-independent apoptosis
  150. A8567 Tenovin-3 Top Seller p53 activator
  151. A4486 SJ 172550 MDMX inhibitor
  152. A3671 Nutlin-3a chiral Top Seller MDM2 inhibitor, antiproliferative and antiproapoptotic
  153. C3192 CBL0137 (hydrochloride) curaxin that activates p53 and inhibits NF-κB
  154. A4203 Tenovin-1 Top Seller SIRT2 inhibitor, activates p53
  155. A1094 tumor protein p53 binding protein fragment [Homo sapiens]/[Mus musculus] P53 binding protein fragment
  156. A4477 Cyclic Pifithrin-α hydrobromide P53 inhibitor
  157. A4482 Pifithrin-μ Inhibitor of p53 binding and anti-apoptotic
  158. A1083 p53 tumor suppressor fragment Regulates cell cycle
  159. A4476 CP 31398 dihydrochloride p53 stabilizer
  160. A8804 AMG232 p53-MDM2 inhibitor, novel
  161. A4208 NSC 319726 Reactivator of mutant p53
  162. A4478 HLI 373 Hdm2 ubiquitin ligase (E3) inhibitor
  163. A4479 MIRA-1 Restorer of wild-type p53 conformation/cellular function
  164. A4480 NSC 146109 hydrochloride Antitumor agent,p53-dependent transcription activator
  165. A4481 PhiKan 083 p53 stabilizer
  166. A4485 RETRA hydrochloride Antitumor agent
  167. A4487 WR 1065 P53/p21waf-1/MDM2 activator
  168. B4677 NVP-CGM097 potent and selective MDM2 inhibitor
  169. B3422 U-73122 inhibitor of phospholipase C, phospholipase A2, and 5-LO (5-lipoxygenase)
  170. B9013 U 73343 negative control of U-73122 for PLC inhibition
  171. A3343 D609 PC-PLC inhibitor
  172. A3833 SPK-601 Potent PC-PLC inhibitor,antimicrobial agent
  173. B9005 RHC 80267 diacylglycerol lipase inhibitor
  174. A8679 CRT 0066101 PKD inhibitor
  175. A8678 CID 755673 PKD inhibitor
  176. A3524 kb NB 142-70 Inhibitor of protein kinase D,selective
  177. A8223 CID 2011756 Top Seller PKD inhibitor
  178. C4165 CRT5 PKD1, PKD2, and PKD3 inhibitor
  179. A3787 Salirasib Inhibitor of active Ras protein
  180. A3947 YM-155 hydrochloride Potent survivin inhibitor
  181. B2092 Doxifluridine oral prodrug of the antineoplastic agent 5-fluorouracil (5-FU)
  182. A4390 Pemetrexed Top Seller TS, DHFR,GARFT and AICARFT inhibitor
  183. A8542 Triflurdine (Viroptic) Anti-herpesvirus antiviral drug
  184. B5892 Nolatrexed (AG-337) Non-classical thymidylate synthase inhibitor
  185. A3707 Pemetrexed disodium hemipenta hydrate Antifolate and antimetabolite agent
  186. A4211 Lenalidomide (CC-5013) Top Seller Antineoplastic agent,inhibits angiogenesis
  187. A4212 Pomalidomide (CC-4047) Top Seller Immunomodulator,antumor/anti-angiogenic
  188. A4213 Necrostatin-1 RIP1 inhibitor
  189. B6194 GSK481 RIP1(Receptor Interacting Protein Kinase 1) inhibitor
  190. B6109 CPI-1189 necrosis factor (TNF) alpha inhibitor
  191. A4216 Thalidomide Immunomodulatory agent,sedative drug,angiogenesis inhibitor
  192. C3129 R-7050 TNF-α receptor signaling antagonist,cell-permeable
  193. A2604 Celastrol Antioxidant, anti-inflammatory and immunosuppressive agent
  194. A3547 Lenalidomide hydrochloride TNF-α secretion inhibitor
  195. A3652 Necrostatin 2 In vitro necroptosis inhibitor
  196. B1188 Lenalidomide hemihydrate TNF-α secretion inhibitor
  197. A3960 Necrostatin 2 racemate In vitro necroptosis inhibitor
  198. A3961 Necrostatin 2 S enantiomer In vitro necroptosis inhibitor
  199. B3921 Roquinimex quinoline derivative immunostimulant
  200. B6090 Bioymifi death receptor DR5 activator
  201. A4473 Melphalan DNA alkylating agent

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