Activation and Inhibition of Apoptosis Several mechanisms have been identified in mammalian cells for the induction of apoptosis. These mechanisms include factors that lead to perturbation of the mitochondria leading to leakage of cytochrome c or factors that directly activate members of the death receptor family. Fas is a member of the tumor necrosis factor (TNF) receptor superfamily, a family of transmembrane receptors that include neurotrophin receptor (p75NTR), TNF-R1, and a variety of other cell surface receptors. Fas Ligand (Fas L) transmits signals to Fas on a target cell by inducing trimerization of Fas. Activation of Fas causes the recruitment of Fas-associated protein with death domain (FADD) via interactions between the death domain of Fas and FADD and is followed by pro-caspase-8 binding to FADD via interactions between the death effector domains (DED) of FADD and pro-caspase-8 leading to the activation of caspase-8. Activation of caspase-8 leads to the activation of other caspases, in effect beginning a caspase cascade that ultimately leads to apoptosis. Caspase-8 activation can also activate Bid, leading to activation of the apoptotic program. Fas-induced apoptosis can be effectively blocked at several stages by either FLICE-inhibitory protein (FLIP), by Bcl-2, or by the cytokine response modifier A (CrmA). In addition, activation of caspase-3 by caspase-9 can be blocked by inhibitor of apoptosis proteins (IAPs). Moreover, the protein kinase, Akt, can be activated by various growth factors and its activity can be blocked by PTEN. Akt functions to promote cell survival through two distinct pathways. Akt inhibits apoptosis by phosphorylating the Bcl-2 family member Bad, which then interacts with 14-3-3 and dissociates from Bcl-xL allowing for cell survival. Alternatively, Akt activates IKK-α that ultimately leads to NF-κB activation and cell survival. Proapoptotic Bcl-2 family members, such as Bax and Bak can promote mitochondrial permeability, while Bcl-2 can inhibit their effects. Upon mitochondrial permeability, apoptogenic factors are released from the mitochondrial inter-membrane space and leak into the cytosol. One factor is cytochrome c, which induces the liberation of protease activators (caspases) that ultimately lead to apoptosis through nuclear damage (DNA fragmentation, DNA mutations). In addition, Smac/Diablo is released and can block IAP inhibition of caspase activity. Mitochondrial permeability is also related to the increased generation of reactive oxygen species (ROS), which plays a role in the degradation phase of apoptosis (i.e. plasma membrane alterations).
Potent inhibitor of heat shock protein 90 (Hsp90). 17-AAG is a less toxic analog than geldanamycin. It induces apoptosis and displays antitumor effects. 17-AAG inhibits the activity of oncogenic proteins such as N-ras, Ki-ras, c-Akt, and p185erB2.
Ara-G is an inducer of apoptosis; inhibitor of DNA synthesis; antineoplastic; and antimetabolite. Ara-G is converted by cellular kinases to the active 5′-triphosphate, Ara-GTP. Incorporation of Ara-GTP into DNA leads to inhibition of DNA synthesis and apoptosis. The cellular accumulation of Ara-GTP is indicative of the clinical response to treatment with nelarabine, the prodrug. The differential accumulation and consequent selective cytotoxicity of Ara-G in T cells has been postulated to be due to the higher accumulation and slower elimination of ara-GTP in these cells. Nelarabine was developed because of poor water solubility of Ara-G, but Ara-G is DMSO-soluble. Nelarabine is approved in the United States for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL).
Bendamustine hydrochloride is a DNA-alkylator with a distinct pattern of activity. Bendamustine activates DNA-damage stress response and apoptosis; inhibits mitotic checkpoints; and induces mitotic catastrophe.
Borrelidin from Streptomyces parvulus, ≥98% (HPLC)
Borrelidin, an 18-membered macrolide-polyketide, is a compound with anti-viral, anti-bacterial, anti-malarial, and anti-angiogenic properties. It is a known inhibitor of bacterial and eukaryal threonyl-tRNA synthetases. Borrelidin induces apoptosis in endothelial cells via the caspase 3 and caspase 8 pathway. In addition, borrelidin strongly inhibits capillary tube formation and also disrupts formed capillary tubes by inducing apoptosis of the tube-forming cells in a rat aorta matrix culture model. In S.cerevisiae, borrelidin inhibits the cyclin-dependent kinase Cdc28/Cln2 with an IC50 of 24 μM, causing the arrest of both haploid and diploid cells in G1 phase and inducing the transcription of amino acid biosynthetic enzymes through a GCN4-dependent pathway.
Borrelidin from Streptomyces sp., ≥95% (HPLC), lyophilized powder
Borrelidin, an 18-membered macrolide-polyketide, is a compound with anti-viral, anti-bacterial, anti-malarial, and anti-angiogenic properties. It is a known inhibitor of bacterial and eukaryal threonyl-tRNA synthetases. Borrelidin induces apoptosis in endothelial cells via the caspase 3 and caspase 8 pathway. In addition, borrelidin strongly inhibits capillary tube formation and also disrupts formed capillary tubes by inducing apoptosis of the tube-forming cells in a rat aorta matrix culture model. In S.cerevisiae, borrelidin inhibits the cyclin-dependent kinase Cdc28/Cln2 with an IC50 of 24 μM, causing the arrest of both haploid and diploid cells in G1 phase and inducing the transcription of amino acid biosynthetic enzymes through a GCN4-dependent pathway.
Brefeldin A from Penicillium brefeldianum, Ready Made Solution, 10 mg/mL in DMSO, 0.2 μm filtered
Brefeldin A (BFA) is a fungal metabolite which disrupts the structure and function of the Golgi apparatus. BFA is an activator of the sphingomyelin cycle. Brefeldin A-mediated apoptosis has been observed in human tumor cells.
An effective PPM1D inhibitor that selectively reduces viability of human tumour cell lines. PPM1D is a phosphatase the gene of which is aberrantly amplified in a range of common cancers. PPM1D activation results in negative regulation of P53 function and other tumour suppressor pathways by selective inactivation of P38 kinase. Therefore, this enzyme can be considered as a potential therapeutic target for cancer. The present study identified a compound, CCT007093 that selectively reduces viability of human tumour cell lines overexpressing PPM1D through inhibition of this phosphatase. The unique advantage of CCT007093 is its ability to mimic the effects of gene-specific PPM1D RNAi, both in its selectivity for human tumour cells that overexpress PPM1D and also by its reliance on an integral P38 pathway.
CHM-1 possess antimitotic antitumor activity. It is a potent and selective antitumor agent in human hepatocellular carcinoma. CHM-1 induces apoptosis, and it binds tubulin and inhibits tubulin polymerization.
Carboxyatractyloside potassium salt ≥98% (HPLC), from Xanthium sibiricum, solid
Carboxylatractyloside is a highly selective inhibitor of cytosolic side-specific mitochondrial ADP/ATP carrier; i.e. adenine nucleotide translocase (ANT); causes stabilization of the c conformation of ANT leading to permeability transition pore (PTP) opening, loss of mitochondrial membrane potential, and apoptosis.
Combretastatin A4 is a vascular disrupting agent (VDA) that targets tumor vasculature to inhibit angiogenesis. It inhibits tubulin polymerization at the colchicine-binding site of beta-tubulin. It has antitumor activity by inhibiting AKT function in human gastric cells. The inhibited AKT activation causes decreased cell proliferation, cell cycle arrest, and reduced in vitro migration/invasiveness and in vivo metastatic ability. Combretastatin A4 is a natural stilbenoid phenol.
Erastin is an antitumor agent selective for tumor cells bearing oncogenic RAS (i.e. HRAS, KRAS). Erastin produces non-apoptotic tumor cell death by altering mitochondrial voltage-dependent anion channel (VDAC) gating allowing cations to enter mitochondria and leading to release of oxidative species causing oxidative cell death.
Second generation glucocorticoid. Used as an anti-inflammatory agent for asthma. Shown to enhance eosinophil apoptosis in a concentration-dependent manner via the glucocorticoid receptor.
IMS2186 is an anti-proliferative and anti-angiogenic. IMS2186 is a novel synthetic compound developed as an anti-CNV drug. The proposed mechanism action, under investigation, is blocking the cell cycle at G2 and inhibition of the production of PGE2/TNF-α. The latter contributing to antiinflammatory and anti-angiogenic effects. IMS2186 inhibits cell growth in vitro in tumor cells, non-transformed fibroblasts, and retinal pigment epithelial cells. IMS2186 inhibits angiogenesis (IC50 = 0.1 μM) and cell migration, which plays a role in many biological processes: inflammation, angiogenesis, and scar formation. The physicochemical structure of IMS2186 showed also that the free drug concentration in a physiological media (e.g., vitreous or saline) is 8–10 μM above the IC50 for all these activities (0.1-3.0 μM). Intraocular injection of IMS2186 could be a long-lasting effective treatment for CNV (choroidal neovascularization) in AMD (age-related macular degeneration) with a reduction in scarring and related visual loss.
Imiquimod is a caspase 3 activator, which directly induces procaspase 3 cleavage to active caspase 3. Imiquimod induces apoptosis in vivo in basal cell carcinoma. Its anti-tumor activity is related to the induction of apoptosis. Imiquimod has anti-angiogenic, anti-inflammatory, anti-viral activities. Imiquimod also acts as an immune response modulator inducing the secretion of various cytokines and chemokines.
H2O: <2 mg/mL DMSO: 4 mg/mL warming to 60 °C for 15 minutes
Native phytosteroid known to have insecticidal properties. Induces apoptosis in cell transfected with wild-type Bax and ecdysone-inducible gene expression systems in mammalian cells and transgenic animals.
Neocarzinostatin from Streptomyces carzinostaticus ≥90% (SDS-PAGE), ~0.5 mg/mL
Neocarzinostatin is a protein-small molecule complex composed of an enediyne chromophore tightly bound to a 113 amino acid single chain protein. The complex possesses antiproliferative and antitumor activity. The chromophore is the active compound, which is responsible for DNA cleavage; while the apoprotein stabilizes and regulates the availability of the labile chromophore. NCS chromophore is bound non-covalently in a cleft of the binding protein andis dissociable. Upon addition of a thiol, the chromophore forms a highly reactive biradical species that can induce sequence-specific single and double strand breaks in DNA. Neocarzinostatin inhibits DNA synthesis and possesses antitumor activity in various human and animal tumors. NCS inhibits cellular proliferation by inducing G2 cell cycle arrest and apoptosis in both human papillomavirus (HPV) positive and negative cell lines.
PCI-34051 is a potent and selective inhibitor of HDAC8. It inhibits cell growth and induces apoptosis only in T-cell-derived tumor lines, such as Jurkat and Hut78, but not in solid tumor lines, or in other hematopoietic tumors such as those derived from B cells, plasma cells or monocytes. This selectivity has not been previously observed for any HDAC inhibitor. The mechanism by which PCI-34051 induces apoptosis in T-cell lines is also novel to the histone deacetylase field; it involves Ca2+ signaling via phospholipase C-gamma1. It is the most potent isoform-selective inhibitor of a histone deacetylase to date, one which is >200-fold selective for HDAC8 in vitro, compared to all the other class I and selected class II HDAC isoforms tested. PCI-34051 does not induce histone or tubulin acetylation.
PRIMA-1 is a selective re-activator of mutant p53 activity in tumor cells, and an inducer of apoptosis and inhibitor of growth of human tumors with mutant p53. Mutations in the tumor suppressor p53 take place in >50% tumor cells. PRIMA-1 selectively restores sequence-specific DNA binding and transactivational activity to mutant p53 proteins at μM concentrations. PRIMA-1 works as a re-activator of the apoptotic function of mutant p53 via conformational modulation of function-specific epitopes.
Prodigiosin hydrochloride from Serratia marcescens, ≥98% (HPLC), powder
Prodigiosin, a tripyrrole red pigment biosynthesized by Serratia marcescens and other bacteria, exhibits antibacterial, anticancer, cytotoxic, immunosuppressive, and antiproliferative activities.1,2,3 Prodigiosin induces apoptosis in hematopoietic cancer cells and cells derived from other human cancers, including gastric and colon with no marked toxicity in nonmalignant cell lines.2,4,5 Morphological analysis of prodigiosin-treated cells demonstrated that prodigiosin induces cell shrinkage, chromatin condensation, reorganization of actin microfilament architecture, and detachment of cells from the cell culture substrate.6 Different targets and mechanisms of action are described for prodigiosin, including induction of single- and double-strand DNA breaks, modulation of pH, regulation of mitogen-activated protein kinase, and inhibition of cell cycle progression.5
Pyocyanin is a redox-active phenazine produced by Pseudomonas aeruginosa, which generates reactive oxygen intermediates that kill mammalian and bacterial cells. In bacteria, pyocyanin acts not only as an antibiotic to inhibit competitors, but also acts as an intracellular signal to activate SoxR, a transcription factor conserved in Proteo- and Actinobacteria. In humans, pyocyanin depletes intracellular stores of NADPH, as it generates intracellular superoxide. It has been found that pyocyanin dramatically accelerates a neutrophil apoptosis both in vitro and in vivo, impairs host defenses, and favors bacteral persistence. pyocyanin induces apoptosis by engagement of lysosomal pathways of cell death, destabilizes neutrophil granules, and releases cathepsin D into the cytosol.
Raltitrexed, also known as Tomudex (AstraZeneca), is a folate-based inhibitor of thymidylate synthase (TS) that is rapidly and extensively metabolized to its more potent polyglutamate derivatives. By inhibiting the formation of precursor pyrimidine nucleotides, raltitrexed prevents the formation of DNA and RNA, which are required for the growth and survival of both normal cells and cancer cells.
Ridaifen-B (RID-B) is a novel tamoxifen (TAM) analog that significantly augments apoptosis-inducing effect of TAM in estrogen receptor (ER)-negatives cells. Ridaifen-B induces mitochondria-involved apoptosis in Jurkat cells, as evidenced by chromatin-condensed cells as well as downstream activation of caspases (caspase-3, -8 and -9) in a dose- and time-dependent manner. At 4 hours of incubation, IC50 for RID-B is 4 muM (30 muM for TAM). And at prolonged treatment of 48 hours, IC50 for RID-B is 0.1 muM.1 In a related report2 on the global anti-tumor activity, RID-B strongly inhibits 39 human cancer cells (JFCR 39), both ER-+ or ER-- at concentrations of equal or less than 1muM (e.g., at 0.38muM for SF-539 [central nervous system], at 0.58muM for HT-29 [colon], at 0.20muM for DMS114 [lung], at 0.21muM for LOX-IMVI [melanoma], and at 0.23muM for MKN74 [stomach]. The binding protein of RID-B that exerts the apoptosis events is currently under investigation.
Rifabutin is an antibiotic; antitumor. Rifabutin interferes with HSP-90 molecular chaperone, enhances ubiquitination and protein degradation, and inactivates bacterial RNA polymerase.
Taurolidine is a broad spectrum antiobiotic with antineoplastic activity, which induces apoptosis and decreases tumor cell proliferation. Taurolidine is mentioned in Nature Chem Bio arcticle as an example of a combination chemical genetics (CCG) study: using the apoptosis inducer taurolidine with TNF-related-apoptosis-inducing ligand (TRAIL) to characterize synergistic responses in many apoptosis related signaling-proteins. Synergistic effects were dependent on the same and on distinct apoptotic pathways which, jointly triggered, result in an amplified response. Several apoptotic pathways, including the TNF-receptor associated and the mitochondrial pathway, were differentially regulated at gene expression level. Additionally transcription factors seem to be influenced, NFKB in particular. Endogenous TRAIL expression was increased by the combination of substances, whereas it is reduced by each single substance. Taurolidine overcame TRAIL resistance. Since the non-toxic taurolidine was able to reduce rhTRAIL toxicity and dose, combined therapy with taurolidine and rhTRAIL may offer new options for cancer treatment. Tauroline is also being used as a tool to study the various mechanisms of apoptosis and necrosis.
Temozolomide is a DNA methylating agent and drug resistance-modifying agent; anti-tumor and anti-angiogenic. Temozolomide induces G2/M arrest and apoptosis through adduction of a methyl group to O6 position of guanine in genomic DNA and functional inactivation of DNA repair protein O(6)-alkylguanine DNA alkyltransferase (AGT) in base excision repair (BER) pathway.
Violacein from Janthinobacterium lividum >98% (violacein (minimum 85% violacein) and deoxyviolacein, HPLC)
Violacein, a violet pigment, is an indole derivative produced by various bacterial strains such as Chromobacterium violaceum, Janthinobacterium lividum, Chromobacterium lividum, and Pseudoalteromonas luteoviolacea. Violacein is a member of a novel class of cytotoxic drugs, which mediate apoptosis.1 Violacein exhibits antitumoral, antibacterial, antiulcerogenic, antileishmanial, and antiviral activities.2,3,4,5 Violacein and its β-cyclodextrin complexes trigger apoptosis and differentiation in HL60 leukemic cells.2 Violacein cytotoxicity is preceded by activation of caspase 8, transcription of NF-κB target genes, and p38-MAPK activation resembling TNF-α signal transduction.1
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