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.
What is Apoptosis? The Apoptotic Pathways and the Caspase Cascade
Targets for Apoptosis
- Pyroptosis(15)
- Caspase(77)
- 14.3.3 Proteins(3)
- Apoptosis Inducers(71)
- Bax(15)
- Bcl-2 Family(136)
- Bcl-xL(13)
- c-RET(15)
- IAP(32)
- KEAP1-Nrf2(73)
- MDM2(21)
- p53(137)
- PC-PLC(6)
- PKD(8)
- RasGAP (Ras- P21)(2)
- Survivin(8)
- Thymidylate Synthase(12)
- TNF-α(141)
- Other Apoptosis(1144)
- Apoptosis Detection(0)
- Caspase Substrate(0)
- APC(6)
- PD-1/PD-L1 interaction(60)
- ASK1(4)
- PAR4(2)
- RIP kinase(47)
- FKBP(22)
Products for Apoptosis
- Cat.No. Product Name Information
- GC47042 Carfilzomib-d8 An internal standard for the quantification of carfilzomib
- GN10733 Carnosic acid
- GC45679 Carubicin An anthracycline with anticancer activity
- GC64110 Carubicin hydrochloride Carubicin hydrochloride is a microbially-derived compound.
- GC35612 Carvacrol Carvacrol is a monoterpenoid phenol isolated from Thymus mongolicus Ronn.
- GC62442 Casein Kinase inhibitor A51 Casein Kinase inhibitor A51 is a potent and orally active casein kinase 1α (CK1α) inhibitor. Casein Kinase inhibitor A51 induces leukemia cell apoptosis, and has potent anti-leukemic activities.
- GC32841 Catechin ((+)-Catechin) Catechin ((+)-Catechin) ((+)-Catechin ((+)-Catechin)) inhibits cyclooxygenase-1 (COX-1) with an IC50 of 1.4 μM.
- GN10543 caudatin
-
GC43149
CAY10404
Many non-steroidal anti-inflammatory drugs (NSAIDs) are potent but non-selective inhibitors of both COX-1 and COX-2 in humans.
- GC43150 CAY10406 CAY10406 is a trifluoromethyl analog of an isatin sulfonamide compound that selectively inhibits caspases 3 and 7.
- GC43154 CAY10443 Mitochondrial release of cytochrome c triggers apoptosis via the assembly of a multimeric complex including caspase-9, Apaf-1, and other components, sometimes called the apoptosome.
- GC43176 CAY10575 CAY10575 (Compound 8) is an IKK2 inhibitor with an IC50 of 0.075 μM.
- GC18530 CAY10616 Resveratrol is a natural polyphenolic antioxidant that has anti-cancer properties.
- GC41317 CAY10625 Survivin is a cellular protein implicated in cell survival by interacting with and inhibiting the apoptotic function of several proteins including Smac/DIABLO, caspase-3, and caspase-7.
- GC43189 CAY10681 Inactivation of the tumor suppressor p53 commonly coincides with increased signaling through NF-κB in cancer.
- GC43190 CAY10682 (±)-Nutlin-3 blocks the interaction of p53 with its negative regulator Mdm2 (IC50 = 90 nM), inducing the expression of p53-regulated genes and blocking the growth of tumor xenografts in vivo.
- GC40650 CAY10706 CAY10706 is a ligustrazine-curcumin hybrid that promotes intracellular reactive oxygen species accumulation preferentially in lung cancer cells.
- GC43198 CAY10717 CAY10717 is a multi-targeted kinase inhibitor that exhibits greater than 40% inhibition of 34 of 104 kinases in an enzymatic assay at a concentration of 100 nM.
- GC43203 CAY10726 CAY10726 is an arylurea fatty acid.
- GC46113 CAY10744 A topoisomerase II-α poison
- GC47053 CAY10746 A ROCK1 and ROCK2 inhibitor
- GC48392 CAY10747 An inhibitor of the Hsp90-Cdc37 protein-protein interaction
- GC47055 CAY10749 CAY10749 (compound 15) is a potent PARP/PI3K inhibitor with pIC50 values of 8.22, 8.44, 8.25, 6.54, 8.13, 6.08 for PARP-1, PARP-2, PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ, respectively. CAY10749 is a highly effective anticancer compound targeted against a wide range of oncologic diseases.
- GC47057 CAY10755 A fungal metabolite with anticancer activity
- GC47061 CAY10763 A dual inhibitor of IDO1 and STAT3 activation
- GC47065 CAY10773 A derivative of sorafenib
- GC49080 CAY10786 CAY10786 (Compound 43) is a GPR52 antagonist with an IC50 of 0.63 μM.
- GC52245 CAY10792 An anticancer agent
- GC14634 CBL0137 curaxin that activates p53 and inhibits NF-κB
-
GC15394
CBL0137 (hydrochloride)
curaxin that activates p53 and inhibits NF-κB
- GC61636 CBR-470-2 CBR-470-2, a glycine-substituted analog, can activate NRF2 signaling.
- GC13648 CC-223 CC-223 (CC-223) is a potent, selective, and orally bioavailable inhibitor of mTOR kinase, with an IC50 value for mTOR kinase of 16 nM. CC-223 inhibits both mTORC1 and mTORC2.
- GC39169 CC-92480 CC-92480 (CC-92480), a cereblon E3 ubiquitin ligase modulating drug (CELMoD), acts as a molecular glue. CC-92480 shows high affinity to cereblon, resulting in potent antimyeloma activity.
- GC19088 CC122 CC122 (CC 122) is an orally active cereblon modulator.
- GC61532 CCI-007 CCI-007 is a small molecule with cytotoxic activity against infant leukemia with MLL rearrangements, with IC50 values of 2.5-6.2 μM in sensitive cells.
- GC12891 CCT007093 PPM1D inhibitor
- GC14566 CCT137690 An inhibitor of Aurora kinases and FLT3
- GC62561 CCT369260 CCT369260 (compound 1) is an orally avtive B-cell lymphoma 6 (BCL6) inhibitor with anti-tumor activity. CCT369260 (compound 1) exhibits an IC50 of 520 nM.
- GC33337 CDC801 CDC801 is a potent and orally active phosphodiesterase 4 (PDE4) and tumor necrosis factor-α (TNF-α) inhibitor with IC50 of 1.1 μM and 2.5 μM, respectively.
- GC39555 CDDO-2P-Im CDDO-2P-Im is an analogue of CDDO-Imidazolide with chemopreventive effect. CDDO-2P-Im can reduce the size and the severity of the lung tumors in mouse lung cancer model.
- GC39556 CDDO-3P-Im CDDO-3P-Im is an analogue of CDDO-Imidazolide with chemopreventive effect. CDDO-3P-Im can reduce the size and the severity of the lung tumors in mouse lung cancer model. CDDO-3P-Im is a orally active necroptosis inhibitor that can be used for the research of ischemia/reperfusion (I/R).
- GC35629 CDDO-dhTFEA CDDO-dhTFEA (RTA dh404) is a synthetic oleanane triterpenoid compound which potently activates Nrf2 and inhibits the pro-inflammatory transcription factor NF-κB.
- GC35630 CDDO-EA CDDO-EA is an NF-E2 related factor 2/antioxidant response element (Nrf2/ARE) activator.
- GC32723 CDDO-Im (RTA-403) CDDO-Im (RTA-403) (RTA-403) is an activator of Nrf2 and PPAR, with Kis of 232 and 344 nM for PPARα and PPARγ.
- GC16625 CDDO-TFEA Nrf2 activator
- GC43217 CDK/CRK Inhibitor CDK/CRK inhibitor is an inhibitor of cyclin-dependent kinases (CDK) and CDK-related kinases (CRK) with IC50 values ranging from 9-839 nM in vitro.
- GC62596 CDK7-IN-3 CDK7-IN-3 (CDK7-IN-3) is an orally active, highly selective, noncovalent CDK7 inhibitor with a KD of 0.065 nM. CDK7-IN-3 shows poor inhibition on CDK2 (Ki=2600 nM), CDK9 (Ki=960 nM), CDK12 (Ki=870 nM). CDK7-IN-3 induces apoptosis in tumor cells and has antitumor activity.
- GC35636 CDK9-IN-7 CDK9-IN-7 (compound 21e) is a selective, highly potent, and orally active CDK9/cyclin T inhibitor (IC50=11 nM), which exhibits more potent over other CDKs (CDK4/cyclinD=148 nM; CDK6/cyclinD=145 nM). CDK9-IN-7 shows antitumor activity without obvious toxicity. CDK9-IN-7 induces NSCLC cell apoptosis, arrests the cell cycle in the G2 phase, and suppresses the stemness properties of NSCLC.
- GC19096 CDKI-73 CDKI-73 is a potent CDK9 inhibitor with Ki of 4 nM; shows selective toxicity to CLL cells(LD50=80 nM) versus normal B cell and normal CD34+ cell(LD50>20 uM).
- GC61865 Cearoin Cearoin increases autophagy and apoptosis through the production of ROS and the activation of ERK.
- GC15083 Celastrol A triterpenoid antioxidant
- GC49152 Celecoxib Carboxylic Acid An inactive metabolite of celecoxib
- GC47070 Celecoxib-d7 An internal standard for the quantification of celecoxib
- GC18392 Cellocidin Cellocidin is an antibiotic originally isolated from S.
- GN10113 Cepharanthine
- GC52489 Ceramide (hydroxy) (bovine spinal cord) A sphingolipid
- GC52485 Ceramide (non-hydroxy) (bovine spinal cord) A sphingolipid
- GC52486 Ceramide Phosphoethanolamine (bovine) A sphingolipid
- GC43229 Ceramide Phosphoethanolamines (bovine) Ceramide phosphoethanolamine (CPE) is an analog of sphingomyelin that contains ethanolamine rather than choline as the head group.
- GC47073 Ceramides (hydroxy) A mixture of hydroxy fatty acid-containing ceramides
- GC43230 Ceramides (non-hydroxy) Ceramides are generated from sphingomyelin through activation of sphingomyelinases or through the de novo synthesis pathway, which requires the coordinated action of serine palmitoyl transferase and ceramide synthase.
- GC49706 Cerberin A cardiac glycoside with cytotoxic and cardiac modulatory activities
- GC60688 Cereblon modulator 1 Cereblon modulator 1 (CC-90009) is a first-in-class GSPT1-selective cereblon (CRBN) E3 ligase modulator, acts as a molecular glue.
-
GC65487
Certolizumab pegol
Certolizumab pegol (Certolizumab) is a recombinant, polyethylene glycolylated, antigen-binding fragment of a humanized monoclonal antibody that selectively targets and neutralizes tumour necrosis factor-α (TNF-α).
- GC11543 Cesium chloride
- GC11710 CFM 4 CFM 4 is a potent small molecular antagonist of CARP-1/APC-2 binding. CFM 4 prevents CARP-1 binding with APC-2, causes G2M cell cycle arrest, and induces apoptosis with an IC50 range of 10-15 μM. CFM 4 also suppresses growth of drug-resistant human breast cancer cells.
- GC35668 CG-200745 CG-200745 (CG-200745) is an orally active, potent pan-HDAC inhibitor which has the hydroxamic acid moiety to bind zinc at the bottom of catalytic pocket. CG-200745 inhibits deacetylation of histone H3 and tubulin. CG-200745 induces the accumulation of p53, promotes p53-dependent transactivation, and enhances the expression of MDM2 and p21 (Waf1/Cip1) proteins. CG-200745 enhances the sensitivity of Gemcitabine-resistant cells to Gemcitabine and 5-Fluorouracil (5-FU; ). CG-200745 induces apoptosis and has anti-tumour effects.
- GC10666 CGP 57380 MNK1 inhibitor, specific and selective
- GC43234 Chaetoglobosin A Chaetoglobosin A is a mycotoxic cytochalasin that was first isolated from the marine-derived endophytic fungus C.
- GC18536 Chartreusin Chartreusin is an antibiotic originally isolated from S.
- GN10463 Chelerythrine
- GC13065 Chelerythrine Chloride Potent inhibitor of PKC and Bcl-xL
- GC31886 Chelidonic acid A pyran with diverse biological activities
- GC40878 Chelidonine Chelidonine is a benzophenanthridine alkaloid that has been isolated from C.
- GC43236 Chevalone B Chevalone B is a meroterpenoid originally isolated from the fungus E.
- GC43237 Chevalone C Chevalone C is a meroterpenoid fungal metabolite originally isolated from E.
- GC64993 Chicoric acid Chicoric acid (Cichoric acid), an orally active dicaffeyltartaric acid, induces reactive oxygen species (ROS) generation.
- GC15739 CHIR-124 Chk1 inhibitor,novel and potent
- GC43239 Chk2 Inhibitor Chk2 Inhibitor (compound 1) is a potent and selective inhibitor of checkpoint kinase 2 (Chk2), with IC50s of 13.5 nM and 220.4 nM for Chk2 and Chk1, respectively. Chk2 Inhibitor can elicit a strong ataxia telangiectasia mutated (ATM)-dependent Chk2-mediated radioprotection effect.
- GC45717 Chlamydocin An HDAC inhibitor
- GC17969 CHM 1 An inhibitor of tubulin polymerization
- GC35682 CHMFL-ABL/KIT-155 CHMFL-ABL/KIT-155 (CHMFL-ABL-KIT-155; compound 34) is a highly potent and orally active type II ABL/c-KIT dual kinase inhibitor (IC50s of 46 nM and 75 nM, respectively), and it also presents significant inhibitory activities to BLK (IC50=81 nM), CSF1R (IC50=227 nM), DDR1 (IC50=116 nM), DDR2 (IC50=325 nM), LCK (IC50=12 nM) and PDGFRβ (IC50=80 nM) kinases. CHMFL-ABL/KIT-155 (CHMFL-ABL-KIT-155) arrests cell cycle progression and induces apoptosis.
- GC64028 Chrysosplenol D Chrysosplenol D is a methoxy flavonoid that induces ERK1/2-mediated apoptosis in triple negative human breast cancer cells.
- GC13408 CI994 (Tacedinaline) An inhibitor of HDAC1, -2, and -3
- GC13589 CID 755673 PKD inhibitor
- GC19436 CID-5721353 CID5721353 is an inhibitor of BCL6 with an IC50 value of 212 μM, which corresponds to a Ki of 147 μM.
- GC32997 Cinchonine ((8R,9S)-Cinchonine) Cinchonine ((8R,9S)-Cinchonine) is a natural compound present in Cinchona bark. Cinchonine ((8R,9S)-Cinchonine) activates endoplasmic reticulum stress-induced apoptosis in human liver cancer cells.
- GC60708 Cinchonine hydrochloride Cinchonine hydrochloride ((8R,9S)-Cinchonine hydrochloride) is a natural alkaloid present in Cinchona bark, with antimalarial activity. Cinchonine hydrochloride activates endoplasmic reticulum (ER) stress-induced apoptosis in human liver cancer cells.
- GC52269 Cinnabarinic Acid-d4 An internal standard for the quantification of cinnabarinic acid
- GC40986 Cinnamamide Cinnamamide is an amide form of of trans-cinnamic acid and a metabolite of Streptomyces.
- GN10189 Cinobufagin
- GC11908 Cisplatin Cisplatin is one of the best and first metal-based chemotherapeutic drugs, which is used for wide range of solid cancers such as testicular, ovarian, bladder, lung, cervical, head and neck cancer, gastric cancer and some other cancers.
-
GC17491
CITCO
Constitutive androstane receptor (CAR) agonist
- GC35703 Citicoline Citicoline (Cytidine diphosphate-choline) is an intermediate in the synthesis of phosphatidylcholine, a component of cell membranes.
- GC31186 Citicoline sodium salt Citicoline sodium salt salt is an intermediate in the synthesis of phosphatidylcholine which is a component of cell membranes and also exerts neuroprotective effects.
- GC43273 Citreoindole Citreoindole is a diketopiperazine metabolite isolated from a hybrid cell fusion of two strains of P.
- GC41514 Citreoviridin Citreoviridin is a mycotoxin isolated from several Penicillium species that has been shown to inhibit the mitochondrial ATP synthetase system.
-
GC14203
Citric acid
Commonly used laboratory reagent
- GC68051 Citric acid-d4
- GC16661 Citrinin A mycotoxin inducing apoptosis