Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.
The activation of caspase-8, a crucial upstream mediator of death receptor signaling, was investigated in epirubicinand Taxol IntroductionApoptosis, a morphologically and biochemically defined form of cell death, 1 plays a role in a wide variety of biologic systems, including tissue homeostasis and regulation of the immune system. 2,3 The process is a highly orchestrated cellular pathway leading to activation of the downstream death machinery. The central mediator and executioner of the death machinery is a proteolytic system involving a family of cysteinyl proteases, called caspases (for review, see Thornberry and Lazebnik 4 ). Triggering of the apoptotic cascade by different death stimuli, such as ionizing radiation 5 and chemotherapeutic drugs, 6 culminates in caspasedependent cleavage of a set of regulatory proteins, degradation of cellular DNA, and complete disassembly of the cell. Thus far, 14 caspase family members have been identified, and some of them, such as caspase-8, mediate apoptotic signals after the activation of death receptors. 7,8 Others, such as caspase-9, are part of the apoptosome and play a role in signal transduction after mitochondrial damage. 9 Recently, an endoplasmic-reticulum-specific pathway of apoptosis has been described that is mediated by caspase-12. 10 Previous data suggest that cytotoxic drugs induce cell death through CD95/Fas-CD95 ligand interaction, 11 and the relevance of this particular death pathway has been shown, for instance, in doxorubicin-induced apoptosis of leukemic T cells. 12 However, other groups were unable to confirm these findings and showed CD95/Fas-independent induction of apoptosis by chemotherapeutic drugs-for example, doxorubicin and etoposide-in Tlymphoma cells. 13,14 The finding that CD95/Fas-signaling and DNA damage induce different apoptosis-signaling pathways has also been shown in a murine and a human B-lymphoma cell line. 15 Furthermore, experimental evidence has been provided that neither FADD 16 nor caspase-8 17 is required for drug-induced apoptosis.In B cells, the induction of apoptosis plays important roles in humoral immunity. In this context, it has been shown that the antigen receptor BCR and the CD95/Fas receptor transduce pro-apoptotic signals in mature B cells (for review, see Tsubata 18 ). We previously showed that activation-induced apoptosis of normal and malignant B lymphocytes upon antigen-receptor ligation is independent of CD95/Fas and CD95/Fas ligand. 19 This has been confirmed by another study demonstrating that B-cell receptormediated apoptosis, in contrast to activation-induced T-cell apoptosis, is not mediated through known death receptor systems, nor does it involve the initial activation of caspase-8. 20 We nevertheless For personal use only. on May 12, 2018. by guest www.bloodjournal.org From observed that drug treatment leads to processing and activation of procaspase-8. We therefore focused our interest on the specific mechanisms leading to apoptotic death after the treatment of immature and mature B-lymphoma cells wi...
The novel luminescent gold(I) complex [N-(N',N'-dimethylaminoethyl)-1,8-naphthalimide-4-sulfide](triethylphosphine)gold(I) was prepared and investigated for its primary biological properties. Cell culture experiments revealed strong antiproliferative effects and induction of apoptosis via mitochondrial pathways. Biodistribution studies by fluorescence microscopy and atomic absorption spectroscopy showed the uptake into cell organelles, an accumulation in the nuclei of tumor cells, and a homogeneous distribution in zebrafish embryos. In vivo monitoring of vascularisation in developing zebrafish embryos revealed a significant anti-angiogenic potency of the complex. Mechanistic experiments indicated that the inhibition of thioredoxin reductase (based on the covalent binding of a gold triethylphosphine fragment) might be involved in the pharmacodynamic behavior of this novel gold species.
Gold complexes with N-heterocyclic carbene (NHC) ligands represent a promising class of metallodrugs for the treatment of cancer or infectious diseases. In this report, the synthesis and the biological evaluation of halogen-containing NHC-Au -Cl complexes are described. The complexes 1 and 5 a-5 f displayed good cytotoxic activity against tumor cells, and cellular uptake studies suggested that an intact Au-NHC fragment is essential for the accumulation of high amounts of both the metal and the NHC ligand. However, the bioavailability was negatively affected by serum components of the cell culture media and was influenced by likely transformations of the complex. One example (5 d) efficiently induced apoptosis in vincristine- and daunorubicin-resistant P-glycoprotein overexpressing Nalm-6 leukemia cells. Cellular uptake studies with this compound showed that both the wild-type and resistant Nalm-6 cells accumulated comparable amounts of gold, indicating that the gold drug was not excreted by P-glycoprotein or other efflux transporters. The effective inhibition of mammalian and bacterial thioredoxin reductases (TrxR) was confirmed for all of the gold complexes. Antibacterial screening of the gold complexes showed a particularly high activity against Gram-positive strains, reflecting their high dependence on an intact Trx/TrxR system. This result is of particular interest as the inhibition of bacterial TrxR represents a relatively little explored mechanism of new anti-infectives.
Dysfunction of the p53/Bax/caspase-3 apoptosis signaling pathway has been shown to play a role in tumorigenesis and tumor progression, ie the development of acquired drug resistance. Low expression of the apoptosis inducer Bax correlates with poor response to therapy and shorter overall survival in solid tumors. In the present study, we analyzed the p53/Bax/caspase-3 pathway in a paired and an unpaired sample series of children with acute lymphoblastic leukemia (ALL) at initial diagnosis and relapse. The data demonstrate that both Bax expression levels and the Bax/Bcl-2 ratio are significantly lower in samples at relapse as compared with samples at initial diagnosis (P = 0.013, Wilcoxon signed rank test (paired samples); P = 0.0039, Mann-Whitney U test (unpaired samples)). The loss of Bax protein expression was not a consequence of Bax frameshift mutations of the G 8 tract and could not be attributed to mutations of the p53 coding sequence (exons 5 to 8) which were detected to a similar extent in de novo ALL samples and at relapse. Analysis of the downstream effector caspase-3 showed loss of spontaneous caspase-3 processing at relapse. Whereas nine out of 14 (64%, paired samples) or 37 out of 77 (48%, unpaired samples) ALL patients at initial diagnosis displayed spontaneous in vivo processing of caspase-3, this was completely absent in patients at relapse (paired samples) or detected in only one out of 34 patients at relapse (2.9%, unpaired samples). We therefore conclude that in ALL relapse a severe disturbance of apoptotic pathways occurs, both at the level of Bax expression and caspase-3 activation. Leukemia (2000) 14, 1606-1613.
The stilbene phytochemicals resveratrol and piceatannol have been reported to possess substantial antitumorigenic and antileukemic activities, respectively. Although recent experimental data revealed the proapoptotic potency of resveratrol, the molecular mechanisms underlying the antileukemic activity have not yet been studied in detail. In the present study, we show that resveratrol, as well as the hydroxylated analog piceatannol, are potent inducers of apoptotic cell death in BJAB Burkittlike lymphoma cells with an ED 50 concentration of 25 M. Further experiments revealed that treatment of BJAB cells with both substances led to a concentration-dependent activation of caspase-3 and mitochondrial permeability transition. Using BJAB cells overexpressing a dominant-negative mutant of the Fas-associated death domain (FADD) adaptor protein to block death receptor-mediated apoptosis, we demonstrate that resveratrol-and piceatannol-induced cell death in these cells is independent of the CD95/Fas signaling pathway. To explore the antileukemic properties of both compounds in more detail, we extended our study to primary, leukemic lymphoblasts. Interestingly, piceatannol but not resveratrol is a very efficient inducer of apoptosis in this ex vivo assay with leukemic lymphoblasts of 21 patients suffering from childhood lymphoblastic leukemia (ALL). Leukemia (2001Leukemia ( ) 15, 1735Leukemia ( -1742
Solid-phase peptide synthesis (SPPS) is a versatile technique for the assembly of small to medium size peptides, that can help in the delivery of bound metal complexes to certain cellular compartments, for example in cancer cells. This work shows a new route to gold-peptide bioconjugates via a non-catalyzed [3 + 2] cycloaddition reaction of gold azides with alkynyl peptides. Gold(I) tetrapeptide conjugates with a mitochondria-targeting sequence were synthesized and display prolonged stability in the presence of thiol-containing biological media. Their antiproliferative potency against selected cancer cells (2-50 mM) corresponds to the lipophilicity of the conjugates. The cellular uptake of Au, determined by atomic absorption spectroscopy (AAS), shows that high initial uptake equals strong cytotoxicity. Respiration and acidification rates react immediately upon treatment with the Au-peptide conjugates, and a terminal breakdown of essential cellular functions is complete within ca. 12 h at most, as observed by online monitoring of the cancer cell metabolism in a microfluidic biosensor device (Bionas sensorchip system). The mode of action of these Au-peptide bioconjugates was elucidated by a variety of biochemical and cell biological experiments. First, a strong selective inhibition of the enzyme thioredoxin reductase (TrxR), a regulator of cellular redox processes, was found. In this context, elevated levels of reactive oxygen species (ROS) and strong effects on the respiration of isolated mouse liver mitochondria were found. These finally lead to cell death via apoptotic pathways, as indicated by flow cytometry, low mitochondrial membrane potential (MMP) and DNA fragmentation. Intriguingly, cisplatin-resistance in p53-mutant MDA-MB231 breast cancer cells could be overcome by the Au-peptide conjugates presented herein.Scheme 2 Fmoc solid-phase peptide synthesis of (phosphine)gold(I) tetrapeptide triazoles 8a-c. Cleavage was effected with TFA-phenol-TIS (75 : 20 : 5) for 1 h in a Schlenk flask under nitrogen. Phenol was added to avoid oxidation of the gold(I) centre under the strongly acidic conditions. Synthesis of (phosphine)gold(I) dipeptides 6a-cTo a flame-dried Schlenk flask 1a (51 mg, 0.1 mmol), alternatively 1b (45 mg, 0.11 mmol) or 1c (43 mg, 0.12 mmol) were added under nitrogen flow together with 1.4 molar equivalents of 3. The mixture was suspended in 10 ml absolute THF and stirred for 4 d under a nitrogen atmosphere protected from light. After completion of the reaction, as indicated by TLC, the solution was evaporated to dryness. The crude product was purified by column chromatography on silica (0.062-0.2 mm) using petroleum ether-ethyl acetate mixtures.
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