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Longsen Chang - One of the best experts on this subject based on the ideXlab platform.
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Amsacrine induced apoptosis of human leukemia u937 cells is mediated by the inhibition of akt and erk induced stabilization of mcl1
Apoptosis, 2017Co-Authors: Yingjung Chen, Chiahui Huang, Longsen ChangAbstract:Previous studies have attributed the anticancer activity of Amsacrine to its inhibitory effect on topoisomerase II. However, 9-aminoacridine derivatives, which have the same structural scaffold as Amsacrine, induce cancer cell apoptosis by altering the expression of BCL2 family proteins. Therefore, in the present study, we assessed whether BCL2 family proteins mediated the cytotoxic effects of Amsacrine on human leukemia U937 cells. Amsacrine-induced apoptosis of U937 cells was characterized by caspase-9 and caspase-3 activation, increased intracellular Ca2+ concentration, mitochondrial depolarization, and MCL1 down-regulation. Amsacrine induced MCL1 down-regulation by decreasing its stability. Further, Amsacrine-treated U937 cells showed AKT degradation and Ca2+-mediated ERK inactivation. Blockade of ERK-mediated phosphorylation of MCL1 inhibited the effect of Pin1 on the stabilization of MCL1, and AKT degradation promoted GSK3β-mediated degradation of MCL1. Restoration of ERK phosphorylation and AKT expression abrogated Amsacrine-induced MCL1 down-regulation. Moreover, MCL1 over-expression inhibited Amsacrine-induced depolarization of mitochondria membrane and increased the viability of Amsacrine-treated cells. Taken together, our data indicate that Amsacrine abolishes ERK- and Pin1-mediated stabilization of MCL1 and promotes GSK3β-mediated degradation of MCL1, leading to activate mitochondria-mediated apoptosis pathway in U937 cells.
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Amsacrine suppresses matrix metalloproteinase 2 mmp 2 mmp 9 expression in human leukemia cells
Journal of Cellular Physiology, 2014Co-Authors: Yingjung Chen, Longsen Chang, Jenhung ChienAbstract:This study explores the suppression mechanism of Amsacrine (4-(9-Acridinylamino)-N-(methanesulfonyl)-m-anisidine hydrochloride) on matrix metalloproteinase-2 (MMP-2) and MMP-9 expression in human leukemia cells. Amsacrine attenuated cell invasion with decreased MMP-2/MMP-9 protein expression and mRNA levels in U937, Jurkat, HL-60, K562, KU812, and MEG-01 cells. Moreover, Amsacrine reduced both MMP-2/MMP-9 promoter luciferase activity and MMP-2/MMP-9 mRNA stability in leukemia cells. Studies on Amsacrine-treated U937 cells revealed that Amsacrine-elicited ROS generation induced JNK and p38 MAPK activation but reduced the phospho-ERK level. Amsacrine-induced ERK inactivation and p38 MAPK/JNK activation were demonstrated to suppress MMP-2/MMP-9 promoter luciferase activity and promote MMP-2/MMP-9 mRNA decay, respectively. p38 MAPK/JNK activation led to up-regulation of protein phosphatase 2A catalytic subunit α (PP2Acα) in Amsacrine-treated U937 cells. Okadaic acid (PP2A inhibitor) treatment increased MMP-2/MMP-9 mRNA stability in Amsacrine-treated cells, whereas PP2Acα over-expression increased MMP-2/MMP-9 mRNA decay. Amsacrine-induced MMP-2/MMP-9 down-regulation was also related to PP2Acα up-regulation on Jurkat, HL-60, K562, KU812, and MEG-01 cells. Collectively, our data indicate that Amsacrine induces MMP-2/MMP-9 down-regulation via simultaneous suppression of genetic transcription and mRNA stability in human leukemia cells. J. Cell. Physiol. 229: 588–598, 2014. © 2013 Wiley Periodicals, Inc.
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Amsacrine suppresses matrix metalloproteinase‐2 (MMP‐2)/MMP‐9 expression in human leukemia cells
Journal of Cellular Physiology, 2014Co-Authors: Yingjung Chen, Jenhung Chien, Longsen ChangAbstract:This study explores the suppression mechanism of Amsacrine (4-(9-Acridinylamino)-N-(methanesulfonyl)-m-anisidine hydrochloride) on matrix metalloproteinase-2 (MMP-2) and MMP-9 expression in human leukemia cells. Amsacrine attenuated cell invasion with decreased MMP-2/MMP-9 protein expression and mRNA levels in U937, Jurkat, HL-60, K562, KU812, and MEG-01 cells. Moreover, Amsacrine reduced both MMP-2/MMP-9 promoter luciferase activity and MMP-2/MMP-9 mRNA stability in leukemia cells. Studies on Amsacrine-treated U937 cells revealed that Amsacrine-elicited ROS generation induced JNK and p38 MAPK activation but reduced the phospho-ERK level. Amsacrine-induced ERK inactivation and p38 MAPK/JNK activation were demonstrated to suppress MMP-2/MMP-9 promoter luciferase activity and promote MMP-2/MMP-9 mRNA decay, respectively. p38 MAPK/JNK activation led to up-regulation of protein phosphatase 2A catalytic subunit α (PP2Acα) in Amsacrine-treated U937 cells. Okadaic acid (PP2A inhibitor) treatment increased MMP-2/MMP-9 mRNA stability in Amsacrine-treated cells, whereas PP2Acα over-expression increased MMP-2/MMP-9 mRNA decay. Amsacrine-induced MMP-2/MMP-9 down-regulation was also related to PP2Acα up-regulation on Jurkat, HL-60, K562, KU812, and MEG-01 cells. Collectively, our data indicate that Amsacrine induces MMP-2/MMP-9 down-regulation via simultaneous suppression of genetic transcription and mRNA stability in human leukemia cells. J. Cell. Physiol. 229: 588–598, 2014. © 2013 Wiley Periodicals, Inc.
Bruce C Baguley - One of the best experts on this subject based on the ideXlab platform.
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carbamate analogues of Amsacrine active against non cycling cells relative activity against topoisomerases iiα and β
Cancer Chemotherapy and Pharmacology, 1999Co-Authors: Rosalind M Turnbull, Bruce C Baguley, Graeme J Finlay, Emma L Meczes, Perenna M Rogers, Richard B Lock, Daniel M Sullivan, Caroline A AustinAbstract:Purpose: Methyl N-(4′-(9-acridinylamino)-phenyl)carbamate hydrochloride (AMCA) and methyl N-(4′-(9-acridinylamino)-2-methoxyphenyl)carbamate hydrochloride (mAMCA) are analogues of the topoisomerase II (topo II) poison Amsacrine, and are distinguished from Amsacrine by their high cytotoxicity towards non-cycling cells. Since mammalian cells contain two forms (α and β) of topo II and the α isoform is down-regulated in non-cycling cells, we have considered whether these carbamate analogues target topo IIβ selectively. Methods: A drug permeable yeast strain (JN394 top2-4) was transformed using a shuttle vector containing either human top2α, human top2α or yeast top2 under the control of a GAL1 promoter. The strain was analysed at a non-permissive temperature, where only the plasmid-borne topo II was active. Results: AMCA and mAMCA produced comparable levels of cell killing with human DNA topo IIα, human DNA topo IIβ and yeast DNA topo II. Two other acridine derivatives N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and its 7-chloro derivative, which like AMCA and mAMCA are able to overcome multidrug resistance mechanisms, were much more active against human DNA topo IIα than against human DNA topo IIβ and yeast DNA topo II. A series of mutant Chinese hamster and human lines with defined topo lesions, including the HL60/MX2 line that lacks topo IIβ expression, was also used to compare resistance to Amsacrine, AMCA and etoposide. Loss of topo IIβ activity had a greater effect on Amsacrine and AMCA than on etoposide. Resistance of murine Lewis lung cultures in exponential and plateau phase was also measured. Loss of topo IIα activity, as measured in both mutant cells expressing lower amounts of enzyme and in cells in plateau phase, resulted in concomitant acquisition of resistance that was greatest for etoposide and least for AMCA. Conclusion: We conclude that the carbamate analogues of Amsacrine recognize both topo IIα and β in cells.
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inhibition of the action of the topoisomerase ii poison Amsacrine by simple aniline derivatives evidence for drug protein interactions
Oncology Research, 1999Co-Authors: Graeme J Finlay, G J Atwell, Bruce C BaguleyAbstract:The action of the anticancer drug Amsacrine appears to involve molecular interactions with both DNA and topoisomerase II. It has been shown previously that DNA intercalators can inhibit the action of Amsacrine and several other topoisomerase II poisons, presumably as a result of interference with the DNA binding sites for the enzyme. We show here that drug molecules such as N-phenylmethanesulfonamide, which mimic the anilino side chain of Amsacrine, inhibit the cytotoxicity against cultured Lewis lung murine carcinoma of Amsacrine, Amsacrine analogues including asulacrine and DACA (N-[2-(dimethylamino)-ethyl]acridine-4-carboxamide dihydrochloride), and etoposide. In contrast, the cytotoxicity of doxorubicin was slightly increased by co-incubation with N-phenylmethanesulfonamide. The cytotoxicity of Amsacrine was also modulated in human Jurkat leukemia, HCT-8 colon, and HT-29 colon cell lines. Because o-AMSA, an Amsacrine analogue containing a methoxy group in the ortho rather than in the meta position, is known to be inactive as an antitumor drug, the abilities of the ortho and meta methoxy-substituted derivatives of methyl-N-phenylcarbamate to reverse the cytotoxicity of Amsacrine, asulacrine, and DACA were compared. The ortho substitution decreased activity while meta substitution slightly increased it, suggesting that the side chains were binding to a similar site to that occupied by Amsacrine. To determine whether the side chain variants actively inhibited the formation of DNA-topoisomerase II covalent complexes, cultured cells were treated with Amsacrine or asulacrine, harvested, and lysed directly on acrylamide gels before electrophoresis and Western blotting to identify non-DNA-bound topoisomerase II. Extractable topoisomerase II was depleted in cells incubated with Amsacrine but partially restored by coculture with methyl-N-phenylcarbamate. The findings are consistent with the hypothesis that low molecular weight molecules can modulate the effects of topoisomerase II poisons by directly interacting with the enzyme.
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cellular responses to methyl n 4 9 acridinylamino 2 methoxyphenyl carbamate hydrochloride an analogue of Amsacrine active against non proliferating cells
European Journal of Cancer, 1997Co-Authors: N Moreland, Graeme J Finlay, M Dragunow, Karen M Holdaway, Bruce C BaguleyAbstract:Abstract The acridine derivative m-AMCA (methyl-N-[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), a carbamate analogue of the toposiomerase II poison Amsacrine, is distinguished by its high cytotoxicity against non-cycling tumour cells. We compared the response of cultured Lewis lung carcinoma cells to m-AMCA, Amsacrine and the topoisomerase I poison camptothecin. The DNA polymerase inhibitor aphidicolin reversed the cytotoxicity of camptothecin fully, that of Amsacrine partially, and that of m-AMCA minimally. The ability of m-AMCA to induce the enzyme poly(ADP-ribose)polymerase (PARP) was markedly lower than that of camptothecin or Amsacrine. Cell cycle responses to m-AMCA and Amsacrine were similar, with slowing of progress through S-phase and arrest in G2-phase. These cell cycle changes were also observed when plateau phase cultures were exposed to drug for 1 h, washed free of drug and cultured in fresh medium, with m-AMCA having a more pronounced effect than Amsacrine and camptothecin having no effect. We also examined the role of p53 protein in the response using cultured human H460 cells. Both mAMCA and Amsacrine induced p53 protein expression in proliferating but not in non-proliferating H460 cells, and induced p21 waf 1 regardless of proliferation status. Both induced G1-phase cell cycle arrest. It is suggested that two cytotoxicity mechanisms can be distinguished using these drugs. The first is specific for S-phase cells, is reversed by aphidicolin and induces PARP activity. The second is cell cycle non-specific, does not induce PARP and is unaffected by aphidicolin. Camptothecin activates only the first, m-AMCA primarily the second and Amsacrine activates both.
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a carbamate analogue of Amsacrine with activity against non cycling cells stimulates topoisomerase ii cleavage at dna sites distinct from those of Amsacrine
European Journal of Cancer, 1997Co-Authors: Bruce C Baguley, Graeme J Finlay, F Leteurtre, J F Riou, Yves PommierAbstract:Abstract AMCA (methyl N -[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), an Amsacrine analogue containing a methylcarbamate rather than a methylsulphonamide side chain, contrasts with Amsacrine, doxorubicin and etoposide in its relatively high cytotoxicity against non-cycling tumour cells. AMCA bound DNA more tightly than Amsacrine, but the DNA base selectivity of binding, as measured by ethidium displacement from poly[dA-dT].[dA-dT] and poly[dG-dC].[dG-dC], was unchanged. AMCA-induced topoisomerase cleavage sites on pBR322, C-MYC and SV40 DNA were investigated using agarose or sequencing gels. DNA fragments were end-labelled, incubated with purified topoisomerase II from different mammalian sources and analysed after treatment with sodium dodecylsulphate/proteinase K. AMCA stimulated the cleavage activity of topoisomerase II, but the DNA sequence selectivity of cleavage was different from that of Amsacrine and other topoisomerase inhibitors. It was similar to that of the methoxy derivative of AMCA, indicating that the changed specificity resulted from the carbamate group rather than from the methoxy group. The pattern of DNA cleavage induced by AMCA was similar for topoisomerase IIα and II β.
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Photo-enhancement of the mutagenicity of 9-anilinoacridine derivatives related to the antitumour agent Amsacrine
Mutation Research, 1992Co-Authors: Yoshihisa Iwamoto, Lynnette R. Ferguson, Amira Pearson, Bruce C BaguleyAbstract:Abstract The frameshift mutagenicity of the DNA intercalating drug proflavine is known to be enhanced by photoirradiation of bacterial cultures. To determine whether this phenomenon was also present in acridine-derived antitumour drugs, cultures of Salmonella typhimurium were exposed to the antileukaemia agent Amsacrine and the experimental agent N -[2-(dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (acridine carboxamide) in the presence or absence of visible light. A small increase in mutagenicity was observed with Amsacrine but not with acridine carboxamide. A series of analogues of Amsacrine were then tested, and a striking relationship was found between the minimum drug concentration for mutagenicity and DNA binding affinity. In each case, photoirradiation was associated with a small increase in mutagenicity. Each of the compounds showing the photo-enhancement effect was capable of reversible one-electron oxidation. It is suggested that this oxidation occurs in bacteria, and that the DNA binding constant of the resulting acridine radical species will increase because of the extra positive charge. This increased DNA binding would be sufficient to explain the photo-enhancement of mutagenicity of these drugs.
Yingjung Chen - One of the best experts on this subject based on the ideXlab platform.
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Amsacrine induced apoptosis of human leukemia u937 cells is mediated by the inhibition of akt and erk induced stabilization of mcl1
Apoptosis, 2017Co-Authors: Yingjung Chen, Chiahui Huang, Longsen ChangAbstract:Previous studies have attributed the anticancer activity of Amsacrine to its inhibitory effect on topoisomerase II. However, 9-aminoacridine derivatives, which have the same structural scaffold as Amsacrine, induce cancer cell apoptosis by altering the expression of BCL2 family proteins. Therefore, in the present study, we assessed whether BCL2 family proteins mediated the cytotoxic effects of Amsacrine on human leukemia U937 cells. Amsacrine-induced apoptosis of U937 cells was characterized by caspase-9 and caspase-3 activation, increased intracellular Ca2+ concentration, mitochondrial depolarization, and MCL1 down-regulation. Amsacrine induced MCL1 down-regulation by decreasing its stability. Further, Amsacrine-treated U937 cells showed AKT degradation and Ca2+-mediated ERK inactivation. Blockade of ERK-mediated phosphorylation of MCL1 inhibited the effect of Pin1 on the stabilization of MCL1, and AKT degradation promoted GSK3β-mediated degradation of MCL1. Restoration of ERK phosphorylation and AKT expression abrogated Amsacrine-induced MCL1 down-regulation. Moreover, MCL1 over-expression inhibited Amsacrine-induced depolarization of mitochondria membrane and increased the viability of Amsacrine-treated cells. Taken together, our data indicate that Amsacrine abolishes ERK- and Pin1-mediated stabilization of MCL1 and promotes GSK3β-mediated degradation of MCL1, leading to activate mitochondria-mediated apoptosis pathway in U937 cells.
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Amsacrine suppresses matrix metalloproteinase 2 mmp 2 mmp 9 expression in human leukemia cells
Journal of Cellular Physiology, 2014Co-Authors: Yingjung Chen, Longsen Chang, Jenhung ChienAbstract:This study explores the suppression mechanism of Amsacrine (4-(9-Acridinylamino)-N-(methanesulfonyl)-m-anisidine hydrochloride) on matrix metalloproteinase-2 (MMP-2) and MMP-9 expression in human leukemia cells. Amsacrine attenuated cell invasion with decreased MMP-2/MMP-9 protein expression and mRNA levels in U937, Jurkat, HL-60, K562, KU812, and MEG-01 cells. Moreover, Amsacrine reduced both MMP-2/MMP-9 promoter luciferase activity and MMP-2/MMP-9 mRNA stability in leukemia cells. Studies on Amsacrine-treated U937 cells revealed that Amsacrine-elicited ROS generation induced JNK and p38 MAPK activation but reduced the phospho-ERK level. Amsacrine-induced ERK inactivation and p38 MAPK/JNK activation were demonstrated to suppress MMP-2/MMP-9 promoter luciferase activity and promote MMP-2/MMP-9 mRNA decay, respectively. p38 MAPK/JNK activation led to up-regulation of protein phosphatase 2A catalytic subunit α (PP2Acα) in Amsacrine-treated U937 cells. Okadaic acid (PP2A inhibitor) treatment increased MMP-2/MMP-9 mRNA stability in Amsacrine-treated cells, whereas PP2Acα over-expression increased MMP-2/MMP-9 mRNA decay. Amsacrine-induced MMP-2/MMP-9 down-regulation was also related to PP2Acα up-regulation on Jurkat, HL-60, K562, KU812, and MEG-01 cells. Collectively, our data indicate that Amsacrine induces MMP-2/MMP-9 down-regulation via simultaneous suppression of genetic transcription and mRNA stability in human leukemia cells. J. Cell. Physiol. 229: 588–598, 2014. © 2013 Wiley Periodicals, Inc.
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Amsacrine suppresses matrix metalloproteinase‐2 (MMP‐2)/MMP‐9 expression in human leukemia cells
Journal of Cellular Physiology, 2014Co-Authors: Yingjung Chen, Jenhung Chien, Longsen ChangAbstract:This study explores the suppression mechanism of Amsacrine (4-(9-Acridinylamino)-N-(methanesulfonyl)-m-anisidine hydrochloride) on matrix metalloproteinase-2 (MMP-2) and MMP-9 expression in human leukemia cells. Amsacrine attenuated cell invasion with decreased MMP-2/MMP-9 protein expression and mRNA levels in U937, Jurkat, HL-60, K562, KU812, and MEG-01 cells. Moreover, Amsacrine reduced both MMP-2/MMP-9 promoter luciferase activity and MMP-2/MMP-9 mRNA stability in leukemia cells. Studies on Amsacrine-treated U937 cells revealed that Amsacrine-elicited ROS generation induced JNK and p38 MAPK activation but reduced the phospho-ERK level. Amsacrine-induced ERK inactivation and p38 MAPK/JNK activation were demonstrated to suppress MMP-2/MMP-9 promoter luciferase activity and promote MMP-2/MMP-9 mRNA decay, respectively. p38 MAPK/JNK activation led to up-regulation of protein phosphatase 2A catalytic subunit α (PP2Acα) in Amsacrine-treated U937 cells. Okadaic acid (PP2A inhibitor) treatment increased MMP-2/MMP-9 mRNA stability in Amsacrine-treated cells, whereas PP2Acα over-expression increased MMP-2/MMP-9 mRNA decay. Amsacrine-induced MMP-2/MMP-9 down-regulation was also related to PP2Acα up-regulation on Jurkat, HL-60, K562, KU812, and MEG-01 cells. Collectively, our data indicate that Amsacrine induces MMP-2/MMP-9 down-regulation via simultaneous suppression of genetic transcription and mRNA stability in human leukemia cells. J. Cell. Physiol. 229: 588–598, 2014. © 2013 Wiley Periodicals, Inc.
Annette K Larsen - One of the best experts on this subject based on the ideXlab platform.
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aurintricarboxylic acid a putative inhibitor of apoptosis is a potent inhibitor of dna topoisomerase ii in vitro and in chinese hamster fibrosarcoma cells
Biochemical Pharmacology, 1995Co-Authors: Youssef Benchokroun, Jeannine Couprie, Annette K LarsenAbstract:Abstract Aurintricarboxylic acid (ATA) is a polyanionic, polyaromatic compound which has been shown to inhibit apoptotic cell death in various cell types induced by a variety of factors. Since ATA is known to be a general inhibitor of nuclease activities in vitro ( id 50 s ranging from 2 to 50 μM), the in vivo effects are usually attributed to inhibition of endogenous endonuclease activities. We show herein that ATA is a potent inhibitor of the nuclear enzyme DNA topoisomerase II. ATA inhibits the catalytic activity of purified yeast topoisomerase II with an id 50 of approx. 75 nM as measured by relaxation assays. ATA does not stabilize the covalent DNA-topoisomerase II reaction intermediate (“cleavable complex”) as do other inhibitors of this enzyme such as 4′-(9-acridinylamino)-methane sulfon- m -anisidide (Amsacrine), 4′-demethyl-epipodophyllotoxin-9-(4,6- O -ethylidene- β -D-glucopyranoside) (etoposide) and ellipticines. In contrast, cleavable complex formation induced by Amsacrine and etoposide is strongly inhibited in the presence of ATA. ATA also prevents the binding of topoisomerase II to DNA and inhibits topoisomerase II-catalysed ATP hydrolysis. The ability of ATA to interfere with more than one step in the catalytic cycle of DNA topoisomerase II may explain its unusual potency as an inhibitor of this enzyme. ATA reduces the number of Amsacrine-induced DNA-protein complexes in intact DC-3F Chinese hamster fibrosarcoma cells and protects these cells from the cytotoxic action of Amsacrine. The effects of ATA on DNA-protein complex formation in living cells appear to be due to the direct interaction of the drug with topoisomerase II, since similar results are found when nuclei from untreated DC-3F cells are exposed to Amsacrine after a short preincubation with ATA. Cells resistant to 9-hydroxyellipticine, which have been shown to possess altered topoisomerase II activity, are approx. 5-fold more resistant to ATA than the sensitive parental cells as shown by colony formation assays. We conclude that ATA is a potent inhibitor of topoisomerase II and that the drug interacts with topoisomerase II in living cells. Our findings raise the possibility that the protective effects of ATA towards apoptotic cell death might, at least in part, involve DNA topoisomerase II.
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suramin is an inhibitor of dna topoisomerase ii in vitro and in chinese hamster fibrosarcoma cells
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Krzysztof Bojanowski, Sophie A Lelievre, Judith Markovits, Jeannine Couprie, Alain Jacqueminsablon, Annette K LarsenAbstract:Abstract The antitrypanosomal and antifiliarial drug suramin is currently under investigation for treatment of advanced malignancies including prostatic cancer, adrenocortical cancer, and some lymphomas and sarcomas. Here we show that suramin is a potent inhibitor of the nuclear enzyme DNA topoisomerase II. Suramin inhibited purified yeast topoisomerase II with an IC50 of about 5 microM, as measured by decatenation or relaxation assays. Suramin did not stabilize the covalent DNA-topoisomerase II reaction intermediate ("cleavable complex"), whereas other inhibitors of this enzyme, such as Amsacrine, etoposide, and the ellipticines, are known to stabilize the intermediate. In contrast, the presence of suramin strongly inhibited the cleavable-complex formation induced by Amsacrine or etoposide. Accumulation of the endogenous cleavable complex was also inhibited. Suramin entered the nucleus of DC-3F Chinese hamster fibrosarcoma cells exposed to radiolabeled suramin for 24 hr as shown by both optic and electron microscopy. The suramin present in the nucleus seemed to interact with topoisomerase II, since suramin reduced the number of Amsacrine-induced protein-associated DNA strand breaks in DC-3F cells and protected these cells from the cytotoxic action of Amsacrine. Cells resistant to 9-hydroxyellipticine, which have been shown to have an altered topoisomerase II activity, are about 7-fold more resistant to suramin than the sensitive parental cells as shown by 72-hr growth inhibition assay. Our results suggest that DNA topoisomerase II is a target of suramin action and that this action may play a role in the cytotoxic activity of suramin.
Jenhung Chien - One of the best experts on this subject based on the ideXlab platform.
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Amsacrine suppresses matrix metalloproteinase 2 mmp 2 mmp 9 expression in human leukemia cells
Journal of Cellular Physiology, 2014Co-Authors: Yingjung Chen, Longsen Chang, Jenhung ChienAbstract:This study explores the suppression mechanism of Amsacrine (4-(9-Acridinylamino)-N-(methanesulfonyl)-m-anisidine hydrochloride) on matrix metalloproteinase-2 (MMP-2) and MMP-9 expression in human leukemia cells. Amsacrine attenuated cell invasion with decreased MMP-2/MMP-9 protein expression and mRNA levels in U937, Jurkat, HL-60, K562, KU812, and MEG-01 cells. Moreover, Amsacrine reduced both MMP-2/MMP-9 promoter luciferase activity and MMP-2/MMP-9 mRNA stability in leukemia cells. Studies on Amsacrine-treated U937 cells revealed that Amsacrine-elicited ROS generation induced JNK and p38 MAPK activation but reduced the phospho-ERK level. Amsacrine-induced ERK inactivation and p38 MAPK/JNK activation were demonstrated to suppress MMP-2/MMP-9 promoter luciferase activity and promote MMP-2/MMP-9 mRNA decay, respectively. p38 MAPK/JNK activation led to up-regulation of protein phosphatase 2A catalytic subunit α (PP2Acα) in Amsacrine-treated U937 cells. Okadaic acid (PP2A inhibitor) treatment increased MMP-2/MMP-9 mRNA stability in Amsacrine-treated cells, whereas PP2Acα over-expression increased MMP-2/MMP-9 mRNA decay. Amsacrine-induced MMP-2/MMP-9 down-regulation was also related to PP2Acα up-regulation on Jurkat, HL-60, K562, KU812, and MEG-01 cells. Collectively, our data indicate that Amsacrine induces MMP-2/MMP-9 down-regulation via simultaneous suppression of genetic transcription and mRNA stability in human leukemia cells. J. Cell. Physiol. 229: 588–598, 2014. © 2013 Wiley Periodicals, Inc.
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Amsacrine suppresses matrix metalloproteinase‐2 (MMP‐2)/MMP‐9 expression in human leukemia cells
Journal of Cellular Physiology, 2014Co-Authors: Yingjung Chen, Jenhung Chien, Longsen ChangAbstract:This study explores the suppression mechanism of Amsacrine (4-(9-Acridinylamino)-N-(methanesulfonyl)-m-anisidine hydrochloride) on matrix metalloproteinase-2 (MMP-2) and MMP-9 expression in human leukemia cells. Amsacrine attenuated cell invasion with decreased MMP-2/MMP-9 protein expression and mRNA levels in U937, Jurkat, HL-60, K562, KU812, and MEG-01 cells. Moreover, Amsacrine reduced both MMP-2/MMP-9 promoter luciferase activity and MMP-2/MMP-9 mRNA stability in leukemia cells. Studies on Amsacrine-treated U937 cells revealed that Amsacrine-elicited ROS generation induced JNK and p38 MAPK activation but reduced the phospho-ERK level. Amsacrine-induced ERK inactivation and p38 MAPK/JNK activation were demonstrated to suppress MMP-2/MMP-9 promoter luciferase activity and promote MMP-2/MMP-9 mRNA decay, respectively. p38 MAPK/JNK activation led to up-regulation of protein phosphatase 2A catalytic subunit α (PP2Acα) in Amsacrine-treated U937 cells. Okadaic acid (PP2A inhibitor) treatment increased MMP-2/MMP-9 mRNA stability in Amsacrine-treated cells, whereas PP2Acα over-expression increased MMP-2/MMP-9 mRNA decay. Amsacrine-induced MMP-2/MMP-9 down-regulation was also related to PP2Acα up-regulation on Jurkat, HL-60, K562, KU812, and MEG-01 cells. Collectively, our data indicate that Amsacrine induces MMP-2/MMP-9 down-regulation via simultaneous suppression of genetic transcription and mRNA stability in human leukemia cells. J. Cell. Physiol. 229: 588–598, 2014. © 2013 Wiley Periodicals, Inc.
