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- Abdallah, Qasem M. A., et al.
(författare)
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Minor structural modifications to alchemix influence mechanism of action and pharmacological activity
- 2012
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 83:11, s. 1514-1522
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Tidskriftsartikel (refereegranskat)abstract
- Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumours. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in Cl supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.
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| 4. |
- Bergh Thorén, Fredrik, 1976, et al.
(författare)
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The anionic amphiphile SDS is an antagonist for the human neutrophil formyl peptide receptor 1.
- 2010
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Ingår i: Biochemical pharmacology. - : Elsevier BV. - 1873-2968 .- 0006-2952. ; 80:3, s. 389-95
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Tidskriftsartikel (refereegranskat)abstract
- The anionic amphiphil sodium dodecyl sulfate (SDS) is commonly used to activate the superoxide-generating NADPH-oxidase complex in cell-free systems, but very little is known about the effects of SDS on intact cells. It was, however, recently shown that SDS causes a translocation and an activation of Rac (a small G-protein) in intact cells, but this signal is not in its own sufficient to activate the oxidase (Nigorikawa et al. (2004) [1]). We found that SDS acted as an antagonist for FPR1, one of the neutrophil members of the formyl peptide receptor family. Accordingly, SDS reduced superoxide anion production induced by the chemoattractant formylmethionyl-leucyl-phenylalanine (fMLF). The receptor specificity of SDS was fairly high, but the concentration range in which it worked was narrow. The length of the carbohydrate chain as well as the charge of the molecule was of importance for the antagonistic effects. Signaling through FPR2, a closely related receptor also expressed in neutrophils, was not inhibited by SDS. On the contrary, the response induced by the FPR2-specific agonist WKYMVM was primed by SDS. The precise mechanism behind the primed state is not known, but might be related to the effects earlier described for SDS on the small G-protein Rac, that is of importance for a proper transduction of the down-stream signals from the occupied receptor.
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| 6. |
- Björkman, Lena, 1965, et al.
(författare)
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Larixol is not an inhibitor of Gαi containing G proteins and lacks effect on signaling mediated by human neutrophil expressed formyl peptide receptors
- 2024
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Ingår i: Biochemical Pharmacology. - 0006-2952 .- 1873-2968. ; 220
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils express several G protein-coupled receptors (GPCRs) connected to intracellular Gαi or Gαq containing G proteins for down-stream signaling. To dampen GPCR mediated inflammatory processes, several inhibitors targeting the receptors and/or their down-stream signals, have been developed. Potent and selective inhibitors for Gαq containing G proteins are available, but potent and specific inhibitors of Gαi containing G proteins are lacking. Recently, Larixol, a compound extracted from the root of Euphorbia formosana, was shown to abolish human neutrophil functions induced by N-formyl-methionyl-leucyl-phenylalanine (fMLF), an agonist recognized by formyl peptide receptor 1 (FPR1) which couple to Gαi containing G proteins. The inhibitory effect was suggested to be due to interference with/inhibition of signals transmitted by βγ complexes of the Gαi containing G proteins coupled to FPR1. In this study, we applied Larixol, obtained from two different commercial sources, to determine the receptor- and G protein- selectivity of this compound in human neutrophils. However, our data show that Larixol not only lacks inhibitory effect on neutrophil responses mediated through FPR1, but also on responses mediated through FPR2, a Gαi coupled GPCR closely related to FPR1. Furthermore, Larixol did not display any features as a selective inhibitor of neutrophil responses mediated through the Gαq coupled GPCRs for platelet activating factor and ATP. Hence, our results imply that the inhibitory effects described for the root extract of Euphorbia formosana are not mediated by Larixol and that the search for a selective inhibitor of G protein dependent signals generated by Gαi coupled neutrophil GPCRs must continue.
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| 7. |
- Burkina, Viktoriia, et al.
(författare)
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In vitro effects of the citrus flavonoids diosmin, naringenin and naringin on the hepatic drug-metabolizing CYP3A enzyme in human, pig, mouse and fish
- 2016
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1873-2968. ; 110-111, s. 109-116
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Tidskriftsartikel (refereegranskat)abstract
- Flavonoids are known to have effects on cytochrome P450 enzymatic activity. However, little effort has been made to examine species differences and the relevance of studies on mammalian and fish microsomes so that extrapolations can be made to humans. Therefore, the effects of several naturally occurring flavonoids on the activity of CYP3A-dependent 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylase (BFCOD) were evaluated in human, pig, mouse, and juvenile rainbow trout sources of hepatic microsomes. Each was exposed to three concentrations (1, 10, and 100 mu M) of diosmin, naringin, and naringenin. Naringenin competitively inhibited BFCOD activity (K-i values were 24.6 mu M in human, 15.6 mu M in pig, and 19.6 mu M in mouse microsomes). In fish, BFCOD activity was inhibited in a noncompetitive manner (K-i = 7 mu M). Neither diosmin nor naringenin affected BFCOD activity in hepatic microsomes from the studied model organisms. These results suggest that dietary flavonoids potentially inhibit the metabolism of clinical drugs. (C) 2016 Elsevier Inc. All rights reserved.
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| 8. |
- Caja, Laia, et al.
(författare)
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The tyrphostin AG1478 inhibits proliferation and induces death of liver tumor cells through EGF receptor-dependent and independent mechanisms.
- 2011
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Ingår i: Biochemical pharmacology. - : Elsevier BV. - 1873-2968 .- 0006-2952. ; 82:11, s. 1583-1592
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death. Different signaling pathways are de-regulated in this pathogenesis, among them the epidermal growth factor receptor one (EGFR/Erb1). Here we show that blockage of this pathway by the tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) in different liver tumor cell lines promotes both inhibition of cell proliferation and induction of cell death, which are coincident with arrest in the G1 phase of the cell cycle, caspase-3 activation and DNA fragmentation. AG1478 up-regulates the expression of the pro-apoptotic member of the BCL-2 family BIM and down-regulates the expression of the anti-apoptotic BCL-XL and MCL1. Furthermore, it also decreases the levels of the caspase inhibitors HIAP2 and XIAP. The treatment of HCC cells with AG1478 enhanced the apoptosis induced by other pro-apoptotic stimuli, such as the physiological cytokine, TGF-β, highly expressed in liver tumors, or the chemotherapeutic drug doxorubicin. The effects observed by AG1478 were broader than the ones seen by silencing of the EGFR with siRNA, which indicates that this drug might act on other targets different from the EGFR. In this same line of evidence, AG1478 retained some cytotoxic effects in cells where EGFR has been targeted knock-down with shRNA. Interestingly, AG1478 preferentially acts on liver tumor cells, being untransformed cells much less responsive to its cytotoxic effects. In conclusion, AG1478 could be a potential therapeutic drug to be used in HCC.
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| 9. |
- Çevik Aras, Hülya, 1975, et al.
(författare)
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A non-peptide receptor inhibitor with selectivity for one of the neutrophil formyl peptide receptors, FPR 1.
- 2012
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Ingår i: Biochemical pharmacology. - : Elsevier BV. - 1873-2968 .- 0006-2952. ; 83:12, s. 1655-1662
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Tidskriftsartikel (refereegranskat)abstract
- The neutrophil formyl peptide receptors (FPR1 and FPR2) are members of the G-protein coupled receptor family. The signals generated by occupied FPRs are both pro-inflammatory and anti-inflammatory. Accordingly, these receptors have become a therapeutic target for the development of novel drugs that may be used to reduce injuries in inflammatory diseases including asthma, rheumatoid arthritis, Alzheimer's disease and cardiovascular diseases. To support the basis for a future pharmacological characterization, we have identified a small molecular non-peptide inhibitor with selectivity for FPR1. We used the FPR1 and FPR2 specific ligands fMLF and WKYMVM, respectively, and an earlier described ratio technique, to determine inhibitory activity combined with selectivity. We show that the compound 3,5-dichloro-N-(2-chloro-5-methyl-phenyl)-2-hydroxy-benzamide (BVT173187) fulfills the criteria for an FPR1 inhibitor selective for FPR1 over FPR2, and it inhibits the same functional repertoire in neutrophils as earlier described peptide antagonists. Accordingly, the new inhibitor reduced neutrophil activation with FPR1 agonists, leading to mobilization of adhesion molecules (CR3) and the generation of superoxide anion from the neutrophil NADPH-oxidase. The effects of a number of structural analogs were determined but these were either without activity or less active/specific than BVT173187. The potency of the new inhibitor for reduction of FPR1 activity was the same as that of the earlier described FPR1 antagonist cyclosporine H, but signaling through the C5aR and CXCR (recognizing IL8) was also affected by BVT173187.
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| 10. |
- Chatzakos, Vicky, 1977-, et al.
(författare)
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Inhibition of sphingosine kinase 1 enhances cytotoxicity, ceramide levels and ROS formation in liver cancer cells treated with selenite
- 2012
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 84:5, s. 712-721
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Tidskriftsartikel (refereegranskat)abstract
- High doses of selenite have been shown to induce cell death in acute myeloid leukemia and lung cancercells. In this study, we combined selenite treatment with modulators of sphingolipid metabolism in thehepatocellular carcinoma cell line Huh7. Treatment with 20 mM of selenite reduced the viability of Huh7cells by half and increased the levels of long chain C14-, C16-, C18- and C18:1- ceramides by two-fold.Inhibition of neutral sphingomyelinase with 3-O-methylsphingosine significantly reduced the cytotoxiceffect of selenite. In line with this result, selenite caused a 2.5-fold increase in the activity of neutralsphingomyelinase. The sphingosine kinase 1 (SK1) inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophe-nyl)thiazole (SK1-II) sensitized the cells to the cytotoxic effects of selenite. Preincubation with 10 mM ofSK1-II prior to treatment with 10 mM of selenite caused induction of apoptosis and gave rise to a 2.5-foldincrease in C14-, C16-, C18- and C18:1- ceramides. Instead, 50 mM of SK1-II combined with 10 mM ofselenite caused accumulation of cells in G1/S phases, but less apoptosis and accumulation of ceramides.The formation of reactive oxygen species (ROS) after treatment with 10 mM of selenite was maximallyenhanced by 1 mM of SK1-II. Moreover, combined treatment with SK1-II and 10 mM of selenitesynergistically reduced the number of viable Huh7 cells, while the non-tumorigenic hepatocyte cell lineMIHA remained unaffected by the same treatment. These results raise the possibility that a combinationof selenite and SK1 inhibitors could be used to treat liver cancer cells, that are regarded as drug resistant,at doses that are non-toxic to normal liver cells.
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