Home >> Signaling Pathways >> Apoptosis

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.

Targets for  Apoptosis

Products for  Apoptosis

  1. Cat.No. Product Name Information
  2. GC10350 TIC10 isomer

    Potent Akt/ERK inhibitor

     TIC10 isomer  Chemical Structure
  3. GC41183 α-Carotene

    α-Carotene is a precursor of vitamin A that has been found in various fruits and vegetables.

    α-Carotene  Chemical Structure
  4. GC45204 α-Ecdysone

    α-Ecdysone is a prohormone of 20-hydroxy ecdysone, an insect-molting, ecdysteroid hormone.

    α-Ecdysone  Chemical Structure
  5. GC45213 α-NETA Choline acetyltransferase (ChAT) mediates the synthesis of the neurotransmitter acetylcholine from acetyl-CoA and choline. α-NETA  Chemical Structure
  6. GC41499 α-Phellandrene α-Phellandrene is a cyclic monoterpene that has been found in various plants, including Cannabis, and has diverse biological activities. α-Phellandrene  Chemical Structure
  7. GC63941 α-Solanine α-Solanine  Chemical Structure
  8. GC41623 β-Elemonic Acid β-Elemonic acid is a triterpene isolated from Boswellia (Burseraceae) that exhibits anticancer activity. β-Elemonic Acid  Chemical Structure
  9. GC62478 Ζ-Stat-2 Ζ-Stat-2  Chemical Structure
  10. GC46008 (±)-Thalidomide-d4 (±)-Thalidomide-d4  Chemical Structure
  11. GC45618 (±)-trans-GK563 (±)-trans-GK563  Chemical Structure
  12. GC45270 (±)10(11)-EDP Ethanolamide (±)10(11)-EDP ethanolamide is an ω-3 endocannabinoid epoxide and cannabinoid (CB) receptor agonist (EC50s = 0.43 and 22.5 nM for CB1 and CB2 receptors, respectively). (±)10(11)-EDP Ethanolamide  Chemical Structure
  13. GC18516 (+)-Aeroplysinin-1 (+)-Aeroplysinin-1 is a metabolite originally isolated from the marine sponge V. (+)-Aeroplysinin-1  Chemical Structure
  14. GC17008 (+)-Apogossypol inhibitor of Bcl-2 family proteins (+)-Apogossypol  Chemical Structure
  15. GC45256 (+)-ar-Turmerone (+)-ar-Turmerone is an aromatic compound from the rhizomes of C. (+)-ar-Turmerone  Chemical Structure
  16. GN10654 (+)-Corynoline Extracted from corydalis sheareri S. Moore;Store the product in sealed,cool and dry condition (+)-Corynoline  Chemical Structure
  17. GC31691 (+)-DHMEQ ((1R,2R,6R)-Dehydroxymethylepoxyquinomicin) (+)-DHMEQ ((1R,2R,6R)-Dehydroxymethylepoxyquinomicin)  Chemical Structure
  18. GC45265 (+)-Goniothalesdiol (+)-Goniothalesdiol, isolated from the bark of the Malaysian tree G. (+)-Goniothalesdiol  Chemical Structure
  19. GC45274 (+)-Pinoresinol   (+)-Pinoresinol  Chemical Structure
  20. GC18749 (+)-Rugulosin (+)-Rugulosin is a pigment and mycotoxin produced by certain fungi. (+)-Rugulosin  Chemical Structure
  21. GC41345 (-)-α-Bisabolol (-)-α-Bisabolol is a sesquiterpene alcohol that has been found in the essential oils of several aromatic plants, including C. (-)-α-Bisabolol  Chemical Structure
  22. GC49502 (-)-β-Sesquiphellandrene A sesquiterpene with antiviral and anticancer activities (-)-β-Sesquiphellandrene  Chemical Structure
  23. GC45244 (-)-(α)-Kainic Acid (hydrate) A potent central nervous system stimulant for induction of seizures (-)-(α)-Kainic Acid (hydrate)  Chemical Structure
  24. GC45246 (-)-Chaetominine (-)-Chaetominine is a cytotoxic alkaloid originally isolated from Chaetomium sp. (-)-Chaetominine  Chemical Structure
  25. GC11965 (-)-Huperzine A NMDA receptor antagonist/AChE inhibitor (-)-Huperzine A  Chemical Structure
  26. GC40698 (-)-Perillyl Alcohol (-)-Perillyl alcohol is a monoterpene alcohol that has been found in lavender essential oil and has diverse biological activities. (-)-Perillyl Alcohol  Chemical Structure
  27. GC40076 (-)-Voacangarine (-)-Voacangarine is an indole alkaloid originally isolated from V. (-)-Voacangarine  Chemical Structure
  28. GC62193 (1S,2S)-Bortezomib (1S,2S)-Bortezomib  Chemical Structure
  29. GC34965 (20S)-Protopanaxatriol (20S)-Protopanaxatriol  Chemical Structure
  30. GC60397 (5Z,2E)-CU-3 (5Z,2E)-CU-3  Chemical Structure
  31. GC60398 (6R)-FR054 (6R)-FR054  Chemical Structure
  32. GC50482 (D)-PPA 1 PD-1/PD-L1 interaction inhibitor (D)-PPA 1  Chemical Structure
  33. GA20156 (D-Ser(tBu)⁶,Azagly¹⁰)-LHRH (free base) (D-Ser(tBu)⁶,Azagly¹⁰)-LHRH (free base)  Chemical Structure
  34. GC41700 (E)-2-(2-Chlorostyryl)-3,5,6-trimethylpyrazine (E)-2-(2-Chlorostyryl)-3,5,6-trimethylpyrazine (CSTMP) is a stilbene derivative with antioxidant and anticancer activities. (E)-2-(2-Chlorostyryl)-3,5,6-trimethylpyrazine  Chemical Structure
  35. GC41268 (E)-2-Hexadecenal Sphingosine-1-phosphate (S1P), a bioactive lipid involved in many signaling processes, is irreversibly degraded by the membrane-bound S1P lyase. (E)-2-Hexadecenal  Chemical Structure
  36. GC41701 (E)-2-Hexadecenal Alkyne (E)-2-Hexadecenal alkyne is an alkyne version of the sphingolipid degradation product (E)-2-hexadecenal that can be used as a click chemistry probe. (E)-2-Hexadecenal Alkyne  Chemical Structure
  37. GC61437 (E)-Methyl 4-coumarate (E)-Methyl 4-coumarate  Chemical Structure
  38. GC34125 (E)-[6]-Dehydroparadol (E)-[6]-Dehydroparadol  Chemical Structure
  39. GN10783 (R) Ginsenoside Rh2 Extracted from Panax ginseng C. A. Mey. dried roots;Store the product in sealed, cool and dry condition (R) Ginsenoside Rh2  Chemical Structure
  40. GC15104 (R)-(+)-Etomoxir sodium salt carnitine palmitoyltransferase I (CPT1) inhibitor (R)-(+)-Etomoxir sodium salt  Chemical Structure
  41. GC34096 (R)-(-)-Gossypol acetic acid (AT-101 (acetic acid)) (R)-(-)-Gossypol acetic acid (AT-101 (acetic acid))  Chemical Structure
  42. GC41716 (R)-CR8 Cyclin-dependent kinases (CDKs) are key regulators of cell cycle progression and are therefore promising targets for cancer therapy. (R)-CR8  Chemical Structure
  43. GC39281 (R)-CR8 trihydrochloride (R)-CR8 trihydrochloride  Chemical Structure
  44. GC41719 (R)-nitro-Blebbistatin (R)-nitro-Blebbistatin is a more stable form of (+)-blebbistatin, which is the inactive form of (-)-blebbistatin. (R)-nitro-Blebbistatin  Chemical Structure
  45. GC60407 (R)-Verapamil D7 hydrochloride (R)-Verapamil D7 hydrochloride  Chemical Structure
  46. GC60408 (R)-Verapamil hydrochloride (R)-Verapamil hydrochloride  Chemical Structure
  47. GC19541 (rac)-Antineoplaston A10

    (rac)-Antineoplaston A10 is the racemate of Antineoplaston A10

    (rac)-Antineoplaston A10  Chemical Structure
  48. GC62528 (Rac)-Hesperetin (Rac)-Hesperetin  Chemical Structure
  49. GC61750 (Rac)-Indoximod (Rac)-Indoximod  Chemical Structure
  50. GC10098 (S)-10-Hydroxycamptothecin inhibitor of topoisomerase I (S)-10-Hydroxycamptothecin  Chemical Structure
  51. GC41557 (S)-3'-amino Blebbistatin (S)-3'-amino Blebbistatin is a more stable and less phototoxic form of (-)-blebbistatin, which is a selective cell-permeable inhibitor of non-muscle myosin II ATPases. (S)-3'-amino Blebbistatin  Chemical Structure
  52. GC41484 (S)-3'-hydroxy Blebbistatin (S)-3'-hydroxy Blebbistatin is a more stable and less phototoxic form of (-)-blebbistatin, which is a selective cell-permeable inhibitor of non-muscle myosin II ATPases. (S)-3'-hydroxy Blebbistatin  Chemical Structure
  53. GC35001 (S)-Gossypol acetic acid (S)-Gossypol acetic acid  Chemical Structure
  54. GC41739 (S)-nitro-Blebbistatin (S)-nitro-Blebbistatin is a more stable form of (-)-blebbistatin, which is a selective cell-permeable inhibitor of non-muscle myosin II ATPases. (S)-nitro-Blebbistatin  Chemical Structure
  55. GC60425 (S)-Verapamil D7 hydrochloride (S)-Verapamil D7 hydrochloride  Chemical Structure
  56. GC60008 (S)-Verapamil hydrochloride (S)-Verapamil hydrochloride  Chemical Structure
  57. GC18787 (±)-Dunnione (±)-Dunnione is a naturally occurring naphthoquinone with diverse biological activities. (±)-Dunnione  Chemical Structure
  58. GC16375 (±)-Jasmonic Acid methyl ester Suppresses proliferation and induces apoptosis (±)-Jasmonic Acid methyl ester  Chemical Structure
  59. GC14154 (±)-Nutlin-3

    MDM2 antagonist, potent and selective

    (±)-Nutlin-3  Chemical Structure
  60. GC19528 1,4-Benzoquinone 1,4-Benzoquinone  Chemical Structure
  61. GC42018 1-O-Octadecyl-2-O-methyl-sn-glycerol 1-O-Octadecyl-2-O-methyl-sn-glycerol is a metabolite of a phosphotidylinositol ether lipid analog (PIA). 1-O-Octadecyl-2-O-methyl-sn-glycerol  Chemical Structure
  62. GC41865 10'-Desmethoxystreptonigrin 10'-Desmethoxystreptonigrin is an antibiotic originally isolated from Streptomyces and a derivative of the antibiotic streptonigrin. 10'-Desmethoxystreptonigrin  Chemical Structure
  63. GC49736 10-acetyl Docetaxel A derivative of paclitaxel and an inhibitor of microtubule depolymerization 10-acetyl Docetaxel  Chemical Structure
  64. GC35057 14-Deoxyandrographolide 14-Deoxyandrographolide  Chemical Structure
  65. GC11988 15-acetoxy Scirpenol mycotoxin that induce apoptotic cell death 15-acetoxy Scirpenol  Chemical Structure
  66. GC41938 15-Lipoxygenase Inhibitor 1 Lipoxygenases (LOs) are non-heme iron-containing dioxygenases that catalyze the oxidation of polyunsaturated fatty acids to generate unsaturated fatty acid hydroperoxides. 15-Lipoxygenase Inhibitor 1  Chemical Structure
  67. GC11720 17-AAG (KOS953) Hsp90 inhibitor 17-AAG (KOS953)  Chemical Structure
  68. GC13044 17-DMAG (Alvespimycin) HCl Hsp90 inhibitor 17-DMAG (Alvespimycin) HCl  Chemical Structure
  69. GC41983 19,20-Epoxycytochalasin D

    19,20-Epoxycytochalasin D is a fungal metabolite that has been found in the endophytic fungus Nemania sp.

    19,20-Epoxycytochalasin D  Chemical Structure
  70. GC39296 1G244 1G244  Chemical Structure
  71. GC41612 2'-O-Methylguanosine 2'-O-Methylguanosine is a modified nucleoside that is produced in tRNAs by the action of tRNA guanosine-2'-O-methyltransferase, using S-adenosyl-L-methionine as a substrate. 2'-O-Methylguanosine  Chemical Structure
  72. GC12258 2,3-DCPE hydrochloride

    2,3-DCPE is a proapoptotic compound with selectivity for cancer cells versus normal human cells

    2,3-DCPE hydrochloride  Chemical Structure
  73. GC40947 2,3-Dimethoxy-5-methyl-p-benzoquinone 2,3-Dimethoxy-5-methyl-p-benzoquinone, also known as coenzyme Q0, is a key intermediate in the synthesis of coenzyme Q, coenzyme Q10, other ubiquinones, and vitamin E. 2,3-Dimethoxy-5-methyl-p-benzoquinone  Chemical Structure
  74. GC46057 2,5-Dihydroxycinnamic Acid phenethyl ester 2,5-Dihydroxycinnamic Acid phenethyl ester  Chemical Structure
  75. GC45324 2,5-dimethyl Celecoxib   2,5-dimethyl Celecoxib  Chemical Structure
  76. GN10065 2-Atractylenolide Extracted from Atractylodes macrocephala Koidz. rhizome;Store the product in sealed, cool and dry condition 2-Atractylenolide  Chemical Structure
  77. GC40675 2-deoxy-Artemisinin 2-deoxy-Artemisinin is an inactive metabolite of the antimalarial agent artemisinin. 2-deoxy-Artemisinin  Chemical Structure
  78. GC17430 2-Deoxy-D-glucose Glycolysis inhibitor 2-Deoxy-D-glucose  Chemical Structure
  79. GC12545 2-HBA indirect inducer of enzymes that catalyze detoxification reactions through the Keap1-Nrf2-ARE pathway. 2-HBA  Chemical Structure
  80. GC38318 2-Methoxycinnamaldehyde 2-Methoxycinnamaldehyde  Chemical Structure
  81. GC15084 2-Methoxyestradiol (2-MeOE2) Apoptotic, antiproliferative and antiangiogenic agent 2-Methoxyestradiol (2-MeOE2)  Chemical Structure
  82. GC15355 2-Trifluoromethyl-2'-methoxychalcone Nrf2 activator 2-Trifluoromethyl-2'-methoxychalcone  Chemical Structure
  83. GN10800 20(S)-NotoginsenosideR2 Extracted from Pseudo-ginseng;Store the product in sealed, cool and dry condition 20(S)-NotoginsenosideR2  Chemical Structure
  84. GC12791 3,3'-Diindolylmethane Anticancer and antineoplastic agent 3,3'-Diindolylmethane  Chemical Structure
  85. GC42237 3,5-dimethyl PIT-1 PtdIns-(3,4,5)-P3 (PIP3) serves as an anchor for the binding of signal transduction proteins bearing pleckstrin homology (PH) domains such as phosphatidylinositol 3-kinase (PI3K) or PTEN. 3,5-dimethyl PIT-1  Chemical Structure
  86. GC17394 3-Nitropropionic acid mitochondrial respiratory complex II (succinate dehydrogenase) inhibitor 3-Nitropropionic acid  Chemical Structure
  87. GC60507 3-O-Methylgallic acid 3-O-Methylgallic acid  Chemical Structure
  88. GC32767 3BDO 3BDO  Chemical Structure
  89. GC45354 4β-Hydroxywithanolide E 4β-Hydroxywithanolide E  Chemical Structure
  90. GC42346 4-bromo A23187

    4-bromo A23187 is a halogenated analog of the highly selective calcium ionophore A23187.

    4-bromo A23187  Chemical Structure
  91. GC30896 4-Hydroxybenzyl alcohol 4-Hydroxybenzyl alcohol  Chemical Structure
  92. GC33815 4-Hydroxyphenylacetic acid 4-Hydroxyphenylacetic acid  Chemical Structure
  93. GC31648 4-Octyl Itaconate A prodrug form of itaconate 4-Octyl Itaconate  Chemical Structure
  94. GC45352 4-oxo Withaferin A   4-oxo Withaferin A  Chemical Structure
  95. GC45353 4-oxo-27-TBDMS Withaferin A   4-oxo-27-TBDMS Withaferin A  Chemical Structure
  96. GC60525 4-Vinylphenol 4-Vinylphenol  Chemical Structure
  97. GC10468 4EGI-1 Competitive eIF4E/eIF4G interaction inhibitor 4EGI-1  Chemical Structure
  98. GN10629 5,7-dihydroxychromone Nrf2/ARE signal activator and PPARγ agonist 5,7-dihydroxychromone  Chemical Structure
  99. GC63972 5,7-Dimethoxyflavanone 5,7-Dimethoxyflavanone  Chemical Structure
  100. GC35147 5-(N,N-Hexamethylene)-amiloride 5-(N,N-Hexamethylene)-amiloride  Chemical Structure
  101. GC45356 5-Aminolevulinic Acid (hydrochloride)   5-Aminolevulinic Acid (hydrochloride)  Chemical Structure

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