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.
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
- 14.3.3 Proteins(6)
- Apoptosis Inducers(45)
- Bcl-2 Family(103)
- RasGAP (Ras- P21)(5)
- Thymidylate Synthase(14)
- Other Apoptosis(915)
- Apoptosis Detection(0)
- Caspase Substrate(0)
- PD-1/PD-L1 interaction(41)
- RIP kinase(44)
Products for Apoptosis
- Cat.No. Product Name Information
Potent Akt/ERK inhibitor
α-Carotene is a precursor of vitamin A that has been found in various fruits and vegetables.
α-Ecdysone is a prohormone of 20-hydroxy ecdysone, an insect-molting, ecdysteroid hormone.
- GC45213 α-NETA Choline acetyltransferase (ChAT) mediates the synthesis of the neurotransmitter acetylcholine from acetyl-CoA and choline.
- GC41499 α-Phellandrene α-Phellandrene is a cyclic monoterpene that has been found in various plants, including Cannabis, and has diverse biological activities.
- GC63941 α-Solanine
- GC41623 β-Elemonic Acid β-Elemonic acid is a triterpene isolated from Boswellia (Burseraceae) that exhibits anticancer activity.
- GC64619 β-Ionone
- GC46008 (±)-Thalidomide-d4
- GC45618 (±)-trans-GK563
- 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).
- GC18516 (+)-Aeroplysinin-1 (+)-Aeroplysinin-1 is a metabolite originally isolated from the marine sponge V.
- GC17008 (+)-Apogossypol inhibitor of Bcl-2 family proteins
- GC45256 (+)-ar-Turmerone (+)-ar-Turmerone is an aromatic compound from the rhizomes of C.
- GN10654 (+)-Corynoline Extracted from corydalis sheareri S. Moore;Store the product in sealed,cool and dry condition
- GC31691 (+)-DHMEQ ((1R,2R,6R)-Dehydroxymethylepoxyquinomicin)
- GC45265 (+)-Goniothalesdiol (+)-Goniothalesdiol, isolated from the bark of the Malaysian tree G.
- GC45274 (+)-Pinoresinol
- GC18749 (+)-Rugulosin (+)-Rugulosin is a pigment and mycotoxin produced by certain fungi.
- GC41345 (-)-α-Bisabolol (-)-α-Bisabolol is a sesquiterpene alcohol that has been found in the essential oils of several aromatic plants, including C.
- GC49502 (-)-β-Sesquiphellandrene A sesquiterpene with antiviral and anticancer activities
- GC45244 (-)-(α)-Kainic Acid (hydrate) A potent central nervous system stimulant for induction of seizures
- GC45246 (-)-Chaetominine (-)-Chaetominine is a cytotoxic alkaloid originally isolated from Chaetomium sp.
- GC11965 (-)-Huperzine A NMDA receptor antagonist/AChE inhibitor
- GC40698 (-)-Perillyl Alcohol (-)-Perillyl alcohol is a monoterpene alcohol that has been found in lavender essential oil and has diverse biological activities.
- GC40076 (-)-Voacangarine (-)-Voacangarine is an indole alkaloid originally isolated from V.
- GC62193 (1S,2S)-Bortezomib
- GC34965 (20S)-Protopanaxatriol
- GC60397 (5Z,2E)-CU-3
- GC60398 (6R)-FR054
- GC50482 (D)-PPA 1 PD-1/PD-L1 interaction inhibitor
- GA20156 (D-Ser(tBu)⁶,Azagly¹⁰)-LHRH (free base)
- 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.
- 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.
- 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.
- GC61437 (E)-Methyl 4-coumarate
- GC34125 (E)--Dehydroparadol
- GN10783 (R) Ginsenoside Rh2 Extracted from Panax ginseng C. A. Mey. dried roots;Store the product in sealed, cool and dry condition
- GC15104 (R)-(+)-Etomoxir sodium salt carnitine palmitoyltransferase I (CPT1) inhibitor
- GC34096 (R)-(-)-Gossypol acetic acid (AT-101 (acetic acid))
- GC65610 (R)-5-Hydroxy-1,7-diphenyl-3-heptanone
- GC41716 (R)-CR8 Cyclin-dependent kinases (CDKs) are key regulators of cell cycle progression and are therefore promising targets for cancer therapy.
- GC39281 (R)-CR8 trihydrochloride
- GC41719 (R)-nitro-Blebbistatin (R)-nitro-Blebbistatin is a more stable form of (+)-blebbistatin, which is the inactive form of (-)-blebbistatin.
- GC60407 (R)-Verapamil D7 hydrochloride
- GC60408 (R)-Verapamil hydrochloride
(rac)-Antineoplaston A10 is the racemate of Antineoplaston A10
- GC62528 (Rac)-Hesperetin
- GC61750 (Rac)-Indoximod
- GC10098 (S)-10-Hydroxycamptothecin inhibitor of topoisomerase I
- 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.
- 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.
- GC52192 (S)-4'-nitro-Blebbistatin
- GC35001 (S)-Gossypol acetic acid
- 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.
- GC60425 (S)-Verapamil D7 hydrochloride
- GC60008 (S)-Verapamil hydrochloride
- GC18787 (±)-Dunnione (±)-Dunnione is a naturally occurring naphthoquinone with diverse biological activities.
- GC16375 (±)-Jasmonic Acid methyl ester Suppresses proliferation and induces apoptosis
MDM2 antagonist, potent and selective
- GC19528 1,4-Benzoquinone
- 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).
- GC41865 10'-Desmethoxystreptonigrin 10'-Desmethoxystreptonigrin is an antibiotic originally isolated from Streptomyces and a derivative of the antibiotic streptonigrin.
- GC49736 10-acetyl Docetaxel A derivative of paclitaxel and an inhibitor of microtubule depolymerization
- GC64726 10-Formyl-5,8-dideazafolic acid
- GC35057 14-Deoxyandrographolide
- GC11988 15-acetoxy Scirpenol mycotoxin that induce apoptotic cell death
- 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.
17-AAG(Geldanamycin), a natural benzoquinone ansamycin antibiotic, is the first established inhibitor of Hsp90.
- GC13044 17-DMAG (Alvespimycin) HCl Hsp90 inhibitor
19,20-Epoxycytochalasin D is a fungal metabolite that has been found in the endophytic fungus Nemania sp.
- GC39296 1G244
- 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.
2,3-DCPE is a proapoptotic compound with selectivity for cancer cells versus normal human cells
- 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.
- GC46057 2,5-Dihydroxycinnamic Acid phenethyl ester
- GC45324 2,5-dimethyl Celecoxib
- GN10065 2-Atractylenolide Extracted from Atractylodes macrocephala Koidz. rhizome;Store the product in sealed, cool and dry condition
- GC40675 2-deoxy-Artemisinin 2-deoxy-Artemisinin is an inactive metabolite of the antimalarial agent artemisinin.
- GC12545 2-HBA indirect inducer of enzymes that catalyze detoxification reactions through the Keap1-Nrf2-ARE pathway.
- GC38318 2-Methoxycinnamaldehyde
- GC15084 2-Methoxyestradiol (2-MeOE2) Apoptotic, antiproliferative and antiangiogenic agent
- GC15355 2-Trifluoromethyl-2'-methoxychalcone Nrf2 activator
- GN10800 20(S)-NotoginsenosideR2 Extracted from Pseudo-ginseng;Store the product in sealed, cool and dry condition
- GC12791 3,3'-Diindolylmethane Anticancer and antineoplastic agent
- 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.
- GC64762 3,6-Dihydroxyflavone
- GC17394 3-Nitropropionic acid mitochondrial respiratory complex II (succinate dehydrogenase) inhibitor
- GC60507 3-O-Methylgallic acid
- GC32767 3BDO
- GC45354 4β-Hydroxywithanolide E
4-bromo A23187 is a halogenated analog of the highly selective calcium ionophore A23187.
- GC30896 4-Hydroxybenzyl alcohol
- GC33815 4-Hydroxyphenylacetic acid
4-Octyl Itaconate (4-OI) is a cell-permeable itaconate derivative. Itaconate and 4-Octyl Itaconate had similar thiol reactivity, making 4-Octyl Itaconate a suitable itaconate surrogate to study its biological function.
- GC45352 4-oxo Withaferin A
- GC45353 4-oxo-27-TBDMS Withaferin A
- GC60525 4-Vinylphenol
- GC10468 4EGI-1 Competitive eIF4E/eIF4G interaction inhibitor