The Experts below are selected from a list of 6801 Experts worldwide ranked by ideXlab platform
Ryuichi Okayasu - One of the best experts on this subject based on the ideXlab platform.
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dna Topoisomerase Inhibitor etoposide enhances gc box dependent promoter activity via sp1 phosphorylation
Cancer Science, 2007Co-Authors: Ichiro Niina, Takayuki Torigoe, Tomonori Igarashi, Tetsuro Wakasugi, Naoya Miyamoto, Tetsuro Onitsuka, Hiroto Izumi, Masaki Shiota, Takeshi Uchiumi, Ryuichi OkayasuAbstract:Modification of transcription factors by anticancer agents plays an important role in both apoptotic and survival signaling. Here we report that both DNA Topoisomerase I and II Inhibitors such as SN-38 and etoposide, but not cisplatin, 5-fluorouracil or actinomycin D, can induce phosphorylation of the transcription factor Sp1. Furthermore, DNA Topoisomerase Inhibitors were shown to transactivate GC-box-dependent promoters such as the SV40 and vascular endothelial growth factor promoters. The phosphorylated form of Sp1 was detectable within 30 min of etoposide treatment and was greatly diminished by the presence of the PI3K Inhibitor wortmannin and by DNA-dependent protein kinase (DNA-PK) knockdown. We also confirmed that the phosphorylated form of DNA-PK was increased by treatment with both etoposide and SN-38. Taken together, these findings demonstrate a novel genomic response to anticancer agents that induce Sp1 phosphorylation, and might contribute to tumor progression and drug resistance. (Cancer Sci 2007; 98: 858–863)
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dna Topoisomerase Inhibitor etoposide enhances gc box dependent promoter activity via sp1 phosphorylation
Cancer Science, 2007Co-Authors: Ichiro Niina, Takayuki Torigoe, Tomonori Igarashi, Tetsuro Wakasugi, Naoya Miyamoto, Hiroto Izumi, Masaki Shiota, Takeshi Uchiumi, Takamitsu Onitsuka, Ryuichi OkayasuAbstract:Modification of transcription factors by anticancer agents plays an important role in both apoptotic and survival signaling. Here we report that both DNA Topoisomerase I and II Inhibitors such as SN-38 and etoposide, but not cisplatin, 5-fluorouracil or actinomycin D, can induce phosphorylation of the transcription factor Sp1. Furthermore, DNA Topoisomerase Inhibitors were shown to transactivate GC-box-dependent promoters such as the SV40 and vascular endothelial growth factor promoters. The phosphorylated form of Sp1 was detectable within 30 min of etoposide treatment and was greatly diminished by the presence of the PI3K Inhibitor wortmannin and by DNA-dependent protein kinase (DNA-PK) knockdown. We also confirmed that the phosphorylated form of DNA-PK was increased by treatment with both etoposide and SN-38. Taken together, these findings demonstrate a novel genomic response to anticancer agents that induce Sp1 phosphorylation, and might contribute to tumor progression and drug resistance.
Rongguang Shao - One of the best experts on this subject based on the ideXlab platform.
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the dual Topoisomerase Inhibitor a35 preferentially and specially targets Topoisomerase 2α by enhancing pre strand and post strand cleavage and inhibiting dna religation
Oncotarget, 2015Co-Authors: Wuli Zhao, Chongwen Bi, Yangbiao Li, Danqing Song, Guohua Jiang, Cheng Ye, Liang Li, Rongguang ShaoAbstract:// Wuli Zhao 1, * , Guohua Jiang 2, * , Chongwen Bi 1 , Yangbiao Li 1 , Jingbo Liu 3 , Cheng Ye 1 , Hongwei He 1 , Liang Li 1 , Danqing Song 1, * , Rongguang Shao 1, * 1 Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China 2 Analysis and Testing Center, Beijing Normal University, Beijing, China 3 China Meitan General Hospital, Beijing, China * These authors have contributed equally to this work Correspondence to: Rongguang Shao, e-mail: rgshao@163.com Keywords: dual Topoisomerase Inhibitor, Topoisomerase2α, cardiotoxicity, DNA religation, enhancing strand cleavage Received: May 24, 2015 Accepted: September 25, 2015 Published: October 07, 2015 ABSTRACT DNA Topoisomerases play a key role in tumor proliferation. Chemotherapeutics targeting Topoisomerases have been widely used in clinical oncology, but resistance and side effects, particularly cardiotoxicity, usually limit their application. Clinical data show that a decrease in Topoisomerase (top) levels is the primary factor responsible for resistance, but in cells there is compensatory effect between the levels of top1 and top2α. Here, we validated cyclizing-berberine A35, which is a dual top Inhibitor and preferentially targets top2α. The impact on the top2α catalytic cycle indicated that A35 could intercalate into DNA but did not interfere with DNA-top binding and top2α ATPase activity. A35 could facilitate DNA-top2α cleavage complex formation by enhancing pre-strand and post-strand cleavage and inhibiting religation, suggesting this compound can be a Topoisomerase poison and had a district mechanism from other Topoisomerase Inhibitors. TARDIS and comet assays showed that A35 could induce cell DNA breakage and DNA-top complexes but had no effect on the cardiac toxicity inducer top2β. Silencing top1 augmented DNA break and silencing top2α decreased DNA break. Further validation in H9c2 cardiac cells showed A35 did not disturb cell proliferation and mitochondrial membrane potency. Additionally, an assay with nude mice further demonstrated A35 did not damage the heart. Our work identifies A35 as a novel skeleton compound dually inhibits Topoisomerases, and predominantly and specially targets top2α by interfering with all cleavage steps and its no cardiac toxicity was verified by cardiac cells and mice heart. A35 could be a novel and effective targeting Topoisomerase agent.
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the dual Topoisomerase Inhibitor a35 preferentially and specially targets Topoisomerase 2α by enhancing pre strand and post strand cleavage and inhibiting dna religation
Oncotarget, 2015Co-Authors: Wuli Zhao, Danqing Song, Guohua Jiang, Jingbo Liu, Rongguang ShaoAbstract:DNA Topoisomerases play a key role in tumor proliferation. Chemotherapeutics targeting Topoisomerases have been widely used in clinical oncology, but resistance and side effects, particularly cardiotoxicity, usually limit their application. Clinical data show that a decrease in Topoisomerase (top) levels is the primary factor responsible for resistance, but in cells there is compensatory effect between the levels of top1 and top2α. Here, we validated cyclizing-berberine A35, which is a dual top Inhibitor and preferentially targets top2α. The impact on the top2α catalytic cycle indicated that A35 could intercalate into DNA but did not interfere with DNA-top binding and top2α ATPase activity. A35 could facilitate DNA-top2α cleavage complex formation by enhancing pre-strand and post-strand cleavage and inhibiting religation, suggesting this compound can be a Topoisomerase poison and had a district mechanism from other Topoisomerase Inhibitors. TARDIS and comet assays showed that A35 could induce cell DNA breakage and DNA-top complexes but had no effect on the cardiac toxicity inducer top2β. Silencing top1 augmented DNA break and silencing top2α decreased DNA break. Further validation in H9c2 cardiac cells showed A35 did not disturb cell proliferation and mitochondrial membrane potency. Additionally, an assay with nude mice further demonstrated A35 did not damage the heart. Our work identifies A35 as a novel skeleton compound dually inhibits Topoisomerases, and predominantly and specially targets top2α by interfering with all cleavage steps and its no cardiac toxicity was verified by cardiac cells and mice heart. A35 could be a novel and effective targeting Topoisomerase agent.
Ichiro Niina - One of the best experts on this subject based on the ideXlab platform.
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dna Topoisomerase Inhibitor etoposide enhances gc box dependent promoter activity via sp1 phosphorylation
Cancer Science, 2007Co-Authors: Ichiro Niina, Takayuki Torigoe, Tomonori Igarashi, Tetsuro Wakasugi, Naoya Miyamoto, Tetsuro Onitsuka, Hiroto Izumi, Masaki Shiota, Takeshi Uchiumi, Ryuichi OkayasuAbstract:Modification of transcription factors by anticancer agents plays an important role in both apoptotic and survival signaling. Here we report that both DNA Topoisomerase I and II Inhibitors such as SN-38 and etoposide, but not cisplatin, 5-fluorouracil or actinomycin D, can induce phosphorylation of the transcription factor Sp1. Furthermore, DNA Topoisomerase Inhibitors were shown to transactivate GC-box-dependent promoters such as the SV40 and vascular endothelial growth factor promoters. The phosphorylated form of Sp1 was detectable within 30 min of etoposide treatment and was greatly diminished by the presence of the PI3K Inhibitor wortmannin and by DNA-dependent protein kinase (DNA-PK) knockdown. We also confirmed that the phosphorylated form of DNA-PK was increased by treatment with both etoposide and SN-38. Taken together, these findings demonstrate a novel genomic response to anticancer agents that induce Sp1 phosphorylation, and might contribute to tumor progression and drug resistance. (Cancer Sci 2007; 98: 858–863)
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dna Topoisomerase Inhibitor etoposide enhances gc box dependent promoter activity via sp1 phosphorylation
Cancer Science, 2007Co-Authors: Ichiro Niina, Takayuki Torigoe, Tomonori Igarashi, Tetsuro Wakasugi, Naoya Miyamoto, Hiroto Izumi, Masaki Shiota, Takeshi Uchiumi, Takamitsu Onitsuka, Ryuichi OkayasuAbstract:Modification of transcription factors by anticancer agents plays an important role in both apoptotic and survival signaling. Here we report that both DNA Topoisomerase I and II Inhibitors such as SN-38 and etoposide, but not cisplatin, 5-fluorouracil or actinomycin D, can induce phosphorylation of the transcription factor Sp1. Furthermore, DNA Topoisomerase Inhibitors were shown to transactivate GC-box-dependent promoters such as the SV40 and vascular endothelial growth factor promoters. The phosphorylated form of Sp1 was detectable within 30 min of etoposide treatment and was greatly diminished by the presence of the PI3K Inhibitor wortmannin and by DNA-dependent protein kinase (DNA-PK) knockdown. We also confirmed that the phosphorylated form of DNA-PK was increased by treatment with both etoposide and SN-38. Taken together, these findings demonstrate a novel genomic response to anticancer agents that induce Sp1 phosphorylation, and might contribute to tumor progression and drug resistance.
Min-liang Kuo - One of the best experts on this subject based on the ideXlab platform.
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activation of c jun nh2 terminal kinase and subsequent cpp32 yama during Topoisomerase Inhibitor β lapachone induced apoptosis through an oxidation dependent pathway
Cancer Research, 1999Co-Authors: Shine-gwo Shiah, Yat-pang Chau, Shuang En Chuang, Shing Chuan Shen, Min-liang KuoAbstract:Beta-lapachone (beta-Lap) has been found to inhibit DNA Topoisomerases (Topos) by a mechanism distinct from that of other commonly known Topo Inhibitors. Here, we demonstrated a pronounced elevation of H2O2 and O2- in human leukemia HL-60 cells treated with beta-Lap. Treatment with other Topo poisons, such as camptothecin (CPT), Vbeta-16, and GL331, did not have the same effect. On the other hand, antioxidant vitamin C (Vit C) treatment effectively antagonized beta-Lap-induced apoptosis. This suggested that a reactive oxygen species (ROS)-related pathway was involved in beta-Lap-induced apoptosis program. We also found that c-Jun NH2-terminal kinase (JNK) but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 was persistently activated in apoptosis induced by beta-Lap. Overexpression of a dominant-negative mutant mitogen-activated protein kinase kinase kinase 1 (MEKK1-DN) or treatment with JNK-specific antisense oligonucleotide or Vit C all prevented beta-Lap-induced JNK activation and the subsequent apoptosis. Only the expression of MEKK1-DN, not Vit C treatment, blocked the JNK activity induced by CPT, Vbeta-16, or GL331. These results confirm again that ROS acts as a mediator for JNK activation during beta-Lap-induced apoptosis. Furthermore, we found that beta-Lap can stimulate CPP32/Yama activity, which was, however, markedly inhibited by the MEKK1-DN expression or Vit C treatment. Again, CPT-induced CPP32/Yama activation can be abolished by MEKK1-DN but not by Vit C treatment. Taken together, these results indicate that beta-Lap but not other Topo Inhibitors triggers apoptosis signaling, i.e., JNK and subsequent CPP32/Yama activation are mediated by the generation of ROS.
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Involvement of Hydrogen Peroxide in Topoisomerase Inhibitor β-lapachone-Induced Apoptosis and Differentiation in Human Leukemia Cells
Free radical biology & medicine, 1998Co-Authors: Yat-pang Chau, Shine-gwo Shiah, Ming-jaw Don, Min-liang KuoAbstract:Beta-Lapachone a novel Topoisomerase Inhibitor, has been found to induce apoptosis in various human cancer cells. In this study we report that a dramatic elevation of hydrogen peroxide (H2O2) in human leukemia HL-60 cells following 1 microM beta-lapachone treatment and that this increase was effectively inhibited by treatment with antioxidant N-acetyl-L-cysteine (NAC), ascorbic acid, alpha-tocopherol. NAC strongly prevented beta-lapachone-induced apoptotic characteristics such as DNA fragmentation and apoptotic morphology. However, treatment of HL-60 cells with another Topoisomerase Inhibitor camptothecin (CPT) did not induce H2O2 production as compared to untreated cells. NAC also failed to block CPT-induced apoptosis. Correlated with these findings, we found that cancer cell lines K562, MCF-7, and SW620, contained high level of intracellular glutathione (GSH), were not elevated in H2O2 and were resistant to apoptosis after treatment with beta-lapachone. In contrast, cancer cell lines such as, HL-60, U937, and Molt-4 which have lower level of GSH, were readily increased of H2O2 and were sensitive to this drug. Furthermore, ectopic overexpression of Bcl-2 in HL-60 cells also attenuated beta-lapachone-induced H2O2 and conferred resistance to beta-lapachone-induced cell death. Beta-Lapachone at the concentration as low as 0.25 microM effectively induced HL-60 cells to undergo monocytic differentiation, as evidenced by CD14 antigenicity and alpha-naphthyl acetate esterase activity. Again, the beta-lapachone-induced monocytic differentiation was suppressed by NAC. These results suggest that intracellular H2O2 generation plays a crucial role in beta-lapachone-induced cell death and differentiation.
Wuli Zhao - One of the best experts on this subject based on the ideXlab platform.
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the dual Topoisomerase Inhibitor a35 preferentially and specially targets Topoisomerase 2α by enhancing pre strand and post strand cleavage and inhibiting dna religation
Oncotarget, 2015Co-Authors: Wuli Zhao, Chongwen Bi, Yangbiao Li, Danqing Song, Guohua Jiang, Cheng Ye, Liang Li, Rongguang ShaoAbstract:// Wuli Zhao 1, * , Guohua Jiang 2, * , Chongwen Bi 1 , Yangbiao Li 1 , Jingbo Liu 3 , Cheng Ye 1 , Hongwei He 1 , Liang Li 1 , Danqing Song 1, * , Rongguang Shao 1, * 1 Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China 2 Analysis and Testing Center, Beijing Normal University, Beijing, China 3 China Meitan General Hospital, Beijing, China * These authors have contributed equally to this work Correspondence to: Rongguang Shao, e-mail: rgshao@163.com Keywords: dual Topoisomerase Inhibitor, Topoisomerase2α, cardiotoxicity, DNA religation, enhancing strand cleavage Received: May 24, 2015 Accepted: September 25, 2015 Published: October 07, 2015 ABSTRACT DNA Topoisomerases play a key role in tumor proliferation. Chemotherapeutics targeting Topoisomerases have been widely used in clinical oncology, but resistance and side effects, particularly cardiotoxicity, usually limit their application. Clinical data show that a decrease in Topoisomerase (top) levels is the primary factor responsible for resistance, but in cells there is compensatory effect between the levels of top1 and top2α. Here, we validated cyclizing-berberine A35, which is a dual top Inhibitor and preferentially targets top2α. The impact on the top2α catalytic cycle indicated that A35 could intercalate into DNA but did not interfere with DNA-top binding and top2α ATPase activity. A35 could facilitate DNA-top2α cleavage complex formation by enhancing pre-strand and post-strand cleavage and inhibiting religation, suggesting this compound can be a Topoisomerase poison and had a district mechanism from other Topoisomerase Inhibitors. TARDIS and comet assays showed that A35 could induce cell DNA breakage and DNA-top complexes but had no effect on the cardiac toxicity inducer top2β. Silencing top1 augmented DNA break and silencing top2α decreased DNA break. Further validation in H9c2 cardiac cells showed A35 did not disturb cell proliferation and mitochondrial membrane potency. Additionally, an assay with nude mice further demonstrated A35 did not damage the heart. Our work identifies A35 as a novel skeleton compound dually inhibits Topoisomerases, and predominantly and specially targets top2α by interfering with all cleavage steps and its no cardiac toxicity was verified by cardiac cells and mice heart. A35 could be a novel and effective targeting Topoisomerase agent.
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the dual Topoisomerase Inhibitor a35 preferentially and specially targets Topoisomerase 2α by enhancing pre strand and post strand cleavage and inhibiting dna religation
Oncotarget, 2015Co-Authors: Wuli Zhao, Danqing Song, Guohua Jiang, Jingbo Liu, Rongguang ShaoAbstract:DNA Topoisomerases play a key role in tumor proliferation. Chemotherapeutics targeting Topoisomerases have been widely used in clinical oncology, but resistance and side effects, particularly cardiotoxicity, usually limit their application. Clinical data show that a decrease in Topoisomerase (top) levels is the primary factor responsible for resistance, but in cells there is compensatory effect between the levels of top1 and top2α. Here, we validated cyclizing-berberine A35, which is a dual top Inhibitor and preferentially targets top2α. The impact on the top2α catalytic cycle indicated that A35 could intercalate into DNA but did not interfere with DNA-top binding and top2α ATPase activity. A35 could facilitate DNA-top2α cleavage complex formation by enhancing pre-strand and post-strand cleavage and inhibiting religation, suggesting this compound can be a Topoisomerase poison and had a district mechanism from other Topoisomerase Inhibitors. TARDIS and comet assays showed that A35 could induce cell DNA breakage and DNA-top complexes but had no effect on the cardiac toxicity inducer top2β. Silencing top1 augmented DNA break and silencing top2α decreased DNA break. Further validation in H9c2 cardiac cells showed A35 did not disturb cell proliferation and mitochondrial membrane potency. Additionally, an assay with nude mice further demonstrated A35 did not damage the heart. Our work identifies A35 as a novel skeleton compound dually inhibits Topoisomerases, and predominantly and specially targets top2α by interfering with all cleavage steps and its no cardiac toxicity was verified by cardiac cells and mice heart. A35 could be a novel and effective targeting Topoisomerase agent.