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(1145)
- 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
- GC17448 AT-406 (SM-406) AT-406 (SM-406) (AT-406) is a potent and orally bioavailable Smac mimetic and an antagonist of IAPs, and it binds to XIAP, cIAP1, and cIAP2 proteins with Ki of 66.4, 1.9, and 5.1 nM, respectively.
- GC15870 AT7519 Multi-CDK inhibitor
- GC13998 AT7519 Hydrochloride A Cdk inhibitor
- GC10638 AT9283 A broad spectrum kinase inhibitor
- GC18133 ATB-346 ATB-346 (ATB-346), an orally active non-steroidal anti-inflammatory drug (NSAID), inhibits cyclooxygenase-1 and 2 (COX-1 and 2).
- GC32704 Atezolizumab (MPDL3280A) Atezolizumab (MPDL3280A) (MPDL3280A) is a selective humanized monoclonal IgG1 antibody against programmed death ligand 1 (PD-L1), used for cancer research.
- GC62499 ATH686 ATH686 is a potent, selective and ATP-competitive FLT3 inhibitor. ATH686 target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3 mutants via induction of apoptosis and cell cycle inhibition. ATH686 has antileukemic effects.
- GC46892 ATRA-BA Hybrid A prodrug form of all-trans retinoic acid and butyric acid
- GN10394 Atractylenolide III
- GC15878 Atractyloside Dipotassium Salt Inhibitor of ADP/ATP translocases
- GC39699 Aurintricarboxylic acid Aurintricarboxylic acid is a nanomolar-potency, allosteric antagonist with selectivity towards αβ-methylene-ATP-sensitive P2X1Rs and P2X3Rs, with IC50s of 8.6 nM and 72.9 nM for rP2X1R and rP2X3R, respectively.
- GC46895 Aurintricarboxylic Acid (ammonium salt) A protein synthesis inhibitor with diverse biological activities
- GC13332 Aurora A Inhibitor I A potent and selective inhibitor of Aurora A kinase
- GC15295 AUY922 (NVP-AUY922) An Hsp90 inhibitor
- GC31719 Avelumab (Anti-Human PD-L1, Human Antibody) Avelumab (Anti-Human PD-L1, Human Antibody) is a fully human IgG1 anti-PD-L1 monoclonal antibody with potential antibody-dependent cell-mediated cytotoxicity.
- GC42880 Avenanthramide-C methyl ester Avenanthramide-C methyl ester is an inhibitor of NF-κB activation that acts by blocking the phosphorylation of IKK and IκB (IC50 ~ 40 μM).
- GC35440 AX-024 AX-024 is an orally available, first-in-class inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC50 ~1 nM.
- GC19046 AX-024 hydrochloride AX-024 hydrochloride is an cytokine release inhibitor which can strongly inhibit the production of interleukin-6 (IL-6), tumor necrosis factor-α (TNFα), interferon-γ (IFN-γ), IL-10 and IL-17A.
- GC17045 AXL1717 A potent and selective inhibitor of IGF-1R
-
GC15055
AZ 628
Raf kinases,potent and ATP-competitive
- GC13433 AZ 960 A JAK2 inhibitor
- GC46901 Azadirachtin A naturally-occurring insecticide
- GC15033 Azathioprine purine synthesis and GTP-binding protein Rac1 activation inhibitor
- GC48971 AZD 1152 (hydrochloride) A prodrug for a potent Aurora B inhibitor
- GC18566 AZD 3147 A dual mTORC1/mTORC2 inhibitor
- GC50109 AZD 5582 dihydrochloride Dimeric Smac mimetic; potent IAP inhibitor
- GC33247 AZD-5991 An Mcl-1 inhibitor
- GC33283 AZD-5991 Racemate AZD-5991 Racemate is the racemate of AZD-5991. AZD-5991 Racemate is a Mcl-1 inhibitor with an IC50 of <3 nM in FRET assay.
- GC33239 AZD-5991 S-enantiomer AZD-5991 S-enantiomer is the less active enantiomer of AZD-5991. AZD-5991 S-enantiomer is a Mcl-1 inhibitor with an IC50 of 6.3 μM in FRET assay and a Kd of 0.98 μM in surface plasmon resonance (SPR) assay.
- GC64938 AZD-7648 AZD-7648 is a potent, orally active, selective DNA-PK inhibitor with an IC50 of 0.6 nM. AZD-7648 induces apoptosis and shows antitumor activity.
- GC12660 AZD1208 A pan-Pim kinase inhibitor
- GC13029 AZD2014 AZD2014 (AZD2014) is an ATP competitive mTOR inhibitor with an IC50 of 2.81 nM. AZD2014 inhibits both mTORC1 and mTORC2 complexes.
- GC33255 AZD4320 AZD4320 is a novel BH3-mimicking dual BCL2/BCLxL inhibitor with IC50s of 26 nM, 17 nM, and 170 nM for KPUM-MS3, KPUM-UH1, and STR-428 cells, respectively.
- GC19050 AZD5582 AZD5582 is a novel class of dimeric Smac mimetics as potent IAP antagonist; binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50 = 15, 21, and 15 nM, respectively).
- GC16380 AZD8055 MTOR inhibitor
- GC19054 Azoramide Azoramide is a small-molecule modulator of the unfolded protein response with antidiabetic activity.
- GC46904 Azoxystrobin A broad-spectrum fungicide
- GC60616 AZT triphosphate AZT triphosphate (3'-Azido-3'-deoxythymidine-5'-triphosphate) is a active triphosphate metabolite of Zidovudine (AZT).
- GC60617 AZT triphosphate TEA AZT triphosphate TEA (3'-Azido-3'-deoxythymidine-5'-triphosphate TEA) is a active triphosphate metabolite of Zidovudine (AZT).
- GC35458 Bacopaside II A triterpene glycoside
- GC34263 Bak BH3 Bak BH3 is derived from the BH3 domain of Bak, can antagonize the function of Bcl-xL in cells.
- GC52344 Bak BH3 (72-87) (human) (trifluoroacetate salt) A Bak-derived peptide
- GC12053 BAM7 A direct activator of Bax
- GN10507 Baohuoside I
- GC15371 Bardoxolone An anti-inflammatory compound that activates Nrf2/ARE signaling
- GC11572 Bardoxolone methyl A synthetic triterpenoid with potent anticancer and antidiabetic activity
- GC60620 Batabulin Batabulin (T138067) is an antitumor agent, which binds covalently and selectively to a subset of the β-tubulin isotypes, thereby disrupting microtubule polymerization. Batabulin affects cell morphology and leads to cell-cycle arrest ultimately induces apoptotic cell death.
- GC60621 Batabulin sodium An inhibitor of tubulin polymerization
- GC12763 Bax channel blocker
- GC16023 Bax inhibitor peptide P5 Bax inhibitor
- GC17195 Bax inhibitor peptide V5 A Bax inhibitor
- GC52476 Bax Inhibitor Peptide V5 (trifluoroacetate salt) A Bax inhibitor
- GC16695 Bax inhibitor peptide, negative control Peptide inhibit Bax translocation to mitochondria
-
GC10345
Bay 11-7085
NK-κB activation inhibitor
-
GC13035
Bay 11-7821
A selective and irreversible NF-κB inhibitor
- GC16389 BAY 61-3606 A Syk inhibitor
- GC42897 BAY 61-3606 (hydrochloride) BAY 61-3606 is a cell-permeable, reversible inhibitor of spleen tyrosine kinase (Syk; Ki = 7.5 nM; IC50 = 10 nM).
- GC12136 BAY 61-3606 dihydrochloride
- GC62164 BAY1082439 BAY1082439 is an orally bioavailable, selective PI3Kα/β/δ inhibitor. BAY1082439 also inhibits mutated forms of PIK3CA. BAY1082439 is highly effective in inhibiting Pten-null prostate cancer growth.
- GC16516 BCH BCH (BCH) is a selective and competitive inhibitor of large neutral amino acid transporter 1 (LAT1) significantly inhibit cellular uptake of amino acids and mTOR phosphorylation, which induces the suppression of cancer growth and apoptosis.
- GC63325 Bcl-xL antagonist 2 Bcl-xL antagonist 2 is a potent, selective, and orally active antagonist of BCL-XL with an IC50 and Ki of 0.091 μM and 65 nM, respectively. Bcl-xL antagonist 2 promotes the apoptosis of cancer cells. Bcl-xL antagonist 2 has the potential for the research of the chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL).
- GC62599 BCL6-IN-4 BCL6-IN-4 is a potent B-cell lymphoma 6 (BCL6) inhibitor with an IC50 of 97 nM. BCL6-IN-4 has anti-tumor activities.
- GC68012 BCL6-IN-7
- GC10721 BDA-366 BDA-366 is a potent Bcl2 antagonist (Ki = 3.3 nM), binding Bcl2-BH4 domain with high affinity and selectivity. BDA-366 induces conformational change in Bcl2 that abrogates its antiapoptotic function, converting it from a survival molecule to a cell death inducer. BDA-366 suppresses growth of lung cancer cells.
- GC42912 Becatecarin Becatecarin is a water-soluble, diethylaminoethyl analog of the antineoplastic antibiotic rebeccamycin.
- GC68369 Belantamab
- GC65031 Belimumab Belimumab (LymphoStat B) is a human IgG1λ monoclonal antibody that inhibits B-cell activating factor (BAFF).
- GC49042 Benastatin A A bacterial metabolite with diverse biological activities
- GC64354 Bendamustine Bendamustine (SDX-105 free base), a purine analogue, is a DNA cross-linking agent. Bendamustine activates DNA-damage stress response and apoptosis. Bendamustine has potent alkylating, anticancer and antimetabolite properties.
- GC10744 Bendamustine HCl Bendamustine HCl (SDX-105), a purine analogue, is a DNA cross-linking agent. Bendamustine HCl activats DNA-damage stress response and apoptosis. Bendamustine HCl has potent alkylating, anticancer and antimetabolite properties.
- GC49781 Benomyl A carbamate pesticide
- GC62451 Benpyrine Benpyrine is a highly specific and orally active TNF-α inhibitor with a KD value of 82.1 μM.
- GC49403 Benzarone An active metabolite of benzbromarone
- GC14930 Benzbromarone TMEM16A/B calcium-activated chloride channel (CaCC) blocker
- GN10520 Benzoylpaeoniflorin
- GC38683 Benzyl isothiocyanate Benzyl isothiocyanate is a member of natural isothiocyanates with antimicrobial activity.
- GN10358 Berbamine hydrochloride
- GN10539 Bergenin
- GC42925 Berteroin Berteroin is a sulforaphane analog found in cruciferous vegetables including Chinese cabbage, rucola salad leaves, and mustard oil.
- GC10734 Beta-Lapachone Beta-Lapachone (ARQ-501;NSC-26326) is a naturally occurring O-naphthoquinone, acts as a topoisomerase I inhibitor, and induces apoptosis by inhibiting cell cycle progression.
- GC35504 Beta-Zearalanol Beta-Zearalenol is an mycotoxin produced by Fusarium spp, which causes apoptosis and oxidative stress in mammalian reproductive cells.
- GN10632 Betulin
- GC10480 Betulinic acid A plant triterpenoid similar to bile acids
- GC48477 Betulinic Acid propargyl ester An alkyne derivative of betulinic acid
- GC48504 Betulinic Aldehyde oxime A derivative of betulin
- GC48520 Betulonaldehyde A pentacyclic triterpenoid
- GC12074 BG45 Novel HDAC3-selective inhibitor
- GC18136 BH3I-1 Bcl-2 or Bcl-XL inhibitor
- GC35511 BI-0252 BI-0252 is an orally active, selective MDM2-p53 inhibitor with an IC50 of 4 nM. BI-0252 can induce tumor regressions in all animals of a mouse SJSA-1 xenograft, with concomitant induction of the tumor protein p53 (TP53) target genes and markers of apoptosis.
- GC17828 BI-847325 dual inhibitor of MEK and Aurora kinases
- GC11224 BI6727(Volasertib) BI6727(Volasertib) (BI 6727) is an orally active, highly potent and ATP-competitive Polo-like kinase 1 (PLK1) inhibitor with an IC50 of 0.87 nM. BI6727(Volasertib) inhibits PLK2 and PLK3 with IC50s of 5 and 56 nM, respectively. BI6727(Volasertib) induces mitotic arrest and apoptosis. BI6727(Volasertib), a dihydropteridinone derivative, shows marked antitumor activity in multiple cancer models.
- GC13636 BIBR 1532 Telomerase inhibitor,novel and selective
- GC60076 Bigelovin Bigelovin, a sesquiterpene lactone isolated from Inula helianthus-aquatica, is a selective retinoid X receptor α agonist. Bigelovin suppresses tumor growth through inducing apoptosis and autophagy via the inhibition of mTOR pathway regulated by ROS generation.
-
GC15987
BIM, Biotinylated
Bim peptide fragment with a biotin moiety attached
-
GC49513
Bim/BOD (IN) Polyclonal Antibody
For immunodetection of Bim-
related proteins - GC52355 BimS BH3 (51-76) (human) (trifluoroacetate salt) A Bim-derived peptide
-
GC14233
BIO-acetoxime
GSK-3α/β inhibitor
- GC67680 BIO8898
- GC18476 Biotin-VAD-FMK Biotin-VAD-FMK is a biotin-conjugated form of the pan-caspase inhibitor Z-VAD(OH)-FMK .
- GC35523 Bioymifi A DR5 agonist