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G L Kellett - One of the best experts on this subject based on the ideXlab platform.
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the human kb multidrug resistant Cell Line kb c1 is hypersensitive to inhibitors of glycosylation
Cancer Letters, 1997Co-Authors: J Bentley, D M Quinn, R S Pitman, J R Warr, G L KellettAbstract:We have previously shown that the hypersensitivity of KB MDR Cells to 2-deoxy-D-glucose is associated with diminished plasma membrane GLUT-1 levels compared with parental, non-MDR Cells. Here we report that MDR Cells are hypersensitive to the N-linked glycosylation inhibitor tunicamycin, which induces partial inhibition of GLUT-1 glycosylation and diminishes GLUT-1-mediated transport. The effect of tunicamycin, which also enhances the hypersensitivity of MDR Cells to 2-deoxy-D-glucose, could not be attributed to alterations in P-glycoprotein activity. The use of agents that act synergistically to diminish the level and activity of GLUT-1 in MDR Cells may be of clinical potential.
S Martelli - One of the best experts on this subject based on the ideXlab platform.
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synthesis and biological evaluation of 2 7 dihydro 3h dibenzo de h cinnoLine 3 7 dione derivatives a novel group of anticancer agents active on a multidrug resistant Cell Line
Bioorganic & Medicinal Chemistry, 2003Co-Authors: Barbara Stefanska, Maria Bontempsgracz, S Martelli, Malgorzata Arciemiuk, Maria Dzieduszycka, Agnieszka Kupiec, Edward BorowskiAbstract:A series of anthrapyridazone derivatives with one or two basic side chains at various positions in the tetracyclic chromophore have been synthesized. The key intermediates in the synthesis are 2,7-dihydro-3H-dibenzo[de,h]cinnoLine-3,7-diones 1, 12 and 15 monosubstituted at position 2 (4d, 16a–e), or 6 (2a–f) or disubstituted at positions 2 and 6 (4a–c) or 2 and 8 (17a–e) with appropriate alkylaminoalkylamines. All analogues showed in vitro cytotoxic activity against murine leukemia (L1210) and human leukemia (K562) Cell Lines. The compounds were also active against human leukemia multidrug resistant (K562/DX) Cell Line with resistance index (RI) in the range 1–3 depending on the compound's structure. Two of the most active in vitro compounds 4a and 11 were tested in vivo against murine P388 leukemia and displayed antileukemic activity comparable with that of Mitoxantrone. DNA-binding assays were performed and DNA affinity data were correlated with the structures of the compounds. The cytoplasmatic membrane affinity values (log k′IAM) have also been determined and the correlation with the resistance indexes discussed. The anthrapyridazones constitute a novel group of antitumor compounds that can overcome multidrug resistance.
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synthesis of dialkylamino alkyl disubstituted pyrimido 5 6 1 de acridines a novel group of anticancer agents active on a multidrug resistant Cell Line
Journal of Medicinal Chemistry, 1995Co-Authors: Ippolito Antonini, Donatella Cola, Paolo Polucci, Maria Bontempsgracz, Edward Borowski, S MartelliAbstract:A series of pyrimidoacridine derivatives with two basic side chains, 7a-e, was synthesized, as potential antitumor drugs, starting from 2-[2-(dimethylamino)ethyl]-6-chloropyrimido[5,6,1-de]acridine-1,3, 7- trione (6) and a suitable (alkylamino)alkylamine. The products 6 and 7a-e showed significant cytotoxic activity in vitro against L1210 leukemia. Compounds 7a,d were 2 orders of magnitude more cytotoxic than ametantrone. All compounds were also examined for their activity on LoVo and resistant LoVo/Dx Cell Lines. Unlike ametantrone, the compounds have shown to be able to overcome the multidrug resistance. Compounds 7a,d, the two most active in vitro, were tested in vivo against murine P388 leukemia showing good activity.
Edward Borowski - One of the best experts on this subject based on the ideXlab platform.
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synthesis and biological evaluation of 2 7 dihydro 3h dibenzo de h cinnoLine 3 7 dione derivatives a novel group of anticancer agents active on a multidrug resistant Cell Line
Bioorganic & Medicinal Chemistry, 2003Co-Authors: Barbara Stefanska, Maria Bontempsgracz, S Martelli, Malgorzata Arciemiuk, Maria Dzieduszycka, Agnieszka Kupiec, Edward BorowskiAbstract:A series of anthrapyridazone derivatives with one or two basic side chains at various positions in the tetracyclic chromophore have been synthesized. The key intermediates in the synthesis are 2,7-dihydro-3H-dibenzo[de,h]cinnoLine-3,7-diones 1, 12 and 15 monosubstituted at position 2 (4d, 16a–e), or 6 (2a–f) or disubstituted at positions 2 and 6 (4a–c) or 2 and 8 (17a–e) with appropriate alkylaminoalkylamines. All analogues showed in vitro cytotoxic activity against murine leukemia (L1210) and human leukemia (K562) Cell Lines. The compounds were also active against human leukemia multidrug resistant (K562/DX) Cell Line with resistance index (RI) in the range 1–3 depending on the compound's structure. Two of the most active in vitro compounds 4a and 11 were tested in vivo against murine P388 leukemia and displayed antileukemic activity comparable with that of Mitoxantrone. DNA-binding assays were performed and DNA affinity data were correlated with the structures of the compounds. The cytoplasmatic membrane affinity values (log k′IAM) have also been determined and the correlation with the resistance indexes discussed. The anthrapyridazones constitute a novel group of antitumor compounds that can overcome multidrug resistance.
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synthesis of dialkylamino alkyl disubstituted pyrimido 5 6 1 de acridines a novel group of anticancer agents active on a multidrug resistant Cell Line
Journal of Medicinal Chemistry, 1995Co-Authors: Ippolito Antonini, Donatella Cola, Paolo Polucci, Maria Bontempsgracz, Edward Borowski, S MartelliAbstract:A series of pyrimidoacridine derivatives with two basic side chains, 7a-e, was synthesized, as potential antitumor drugs, starting from 2-[2-(dimethylamino)ethyl]-6-chloropyrimido[5,6,1-de]acridine-1,3, 7- trione (6) and a suitable (alkylamino)alkylamine. The products 6 and 7a-e showed significant cytotoxic activity in vitro against L1210 leukemia. Compounds 7a,d were 2 orders of magnitude more cytotoxic than ametantrone. All compounds were also examined for their activity on LoVo and resistant LoVo/Dx Cell Lines. Unlike ametantrone, the compounds have shown to be able to overcome the multidrug resistance. Compounds 7a,d, the two most active in vitro, were tested in vivo against murine P388 leukemia showing good activity.
Yukihiro Terada - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Uterine Sarcoma Cell Growth through Suppression of Endogenous Tyrosine Kinase B Signaling
2012Co-Authors: Kenichi Makino, Kazuhiro Kawamura, Wataru Sato, Nanami Kawamura, Toshio Fujimoto, Yukihiro TeradaAbstract:Uterine leiomyosarcoma is an aggressive tumor typically found at advanced stages due to difficulties with early diagnosis. Because uterine leiomyosarcoma is resistant to conventional radiation and chemotherapy, the development of more potent medical therapeutics is anticipated. Using quantitative real-time RT-PCR and immunostaining, we found the expression of brain-derived neurotrophic factor (BDNF) and neurotropin-4/5, together with their receptor, tyrosine kinase B (TrkB), in different uterine sarcoma Cell Lines and primary tumor samples from uterine leiomyosarcoma patients. We noted that levels of BDNF were more abundant than those of neurotropin-4/5. Moreover, the expression of TrkB and its ligands was elevated in a Multidrug-Resistant Cell Line and samples obtained from patients with leiomyosarcoma. In cultured uterine sarcoma Cells, inhibition of endogenous TrkB signaling by treatment with either the soluble TrkB ectodomain or the Trk receptor inhibitor, K252a, suppressed Cell proliferation and increased apoptosis based on Cell viability and proliferation, in situ terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick end-labeling and caspase-3/7 assays, whereas an inactive plasma membrane nonpermeable K252b was ineffective. Correspondingly, treatment with exogenous BDNF increased Cell proliferation. In in vivo studies in athymic nude mice bearing Multidrug-Resistant uterine sarcoma Cell tumors, we demonstrate suppression of tumor growth by treatment with K252a, but not K252b, as reflected by decreased Cell proliferation and increased levels of apoptosis and caspase-3/7 activities without obvious side effects. Our findings indicated that endogenous signaling of the TrkB pathway contributed to uterine sarcoma Cell growth, and inhibition of TrkB signaling in these tumors could provide a novel medical therapy for patients with uterine sarcomas.
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Inhibition of uterine sarcoma Cell growth through suppression of endogenous tyrosine kinase B signaling
2012Co-Authors: Kenichi Makino, Kazuhiro Kawamura, Wataru Sato, Nanami Kawamura, Toshio Fujimoto, Yukihiro TeradaAbstract:Uterine leiomyosarcoma is an aggressive tumor typically found at advanced stages due to difficulties with early diagnosis. Because uterine leiomyosarcoma is resistant to conventional radiation and chemotherapy, the development of more potent medical therapeutics is anticipated. Using quantitative real-time RT-PCR and immunostaining, we found the expression of brain-derived neurotrophic factor (BDNF) and neurotropin-4/5, together with their receptor, tyrosine kinase B (TrkB), in different uterine sarcoma Cell Lines and primary tumor samples from uterine leiomyosarcoma patients. We noted that levels of BDNF were more abundant than those of neurotropin-4/5. Moreover, the expression of TrkB and its ligands was elevated in a Multidrug-Resistant Cell Line and samples obtained from patients with leiomyosarcoma. In cultured uterine sarcoma Cells, inhibition of endogenous TrkB signaling by treatment with either the soluble TrkB ectodomain or the Trk receptor inhibitor, K252a, suppressed Cell proliferation and increased apoptosis based on Cell viability and proliferation, in situ terminal deoxynucleotidyl transferase-mediated 29-deoxyuridine 59-triphosphate nick end-labeling and caspase-3/7 assays, whereas an inactive plasma membrane nonpermeable K252b was ineffective. Correspondingly, treatment with exogenous BDNF increased Cell proliferation. In in vivo studies in athymic nude mice bearing Multidrug-Resistant uterine sarcoma Cell tumors, we demonstrate suppression of tumor growth by treatment with K252a, but not K252b, as reflected by decreased Cell proliferation and increased levels of apoptosis and caspase-3/7 activities without obvious side effects. Our finding
J Bentley - One of the best experts on this subject based on the ideXlab platform.
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the human kb multidrug resistant Cell Line kb c1 is hypersensitive to inhibitors of glycosylation
Cancer Letters, 1997Co-Authors: J Bentley, D M Quinn, R S Pitman, J R Warr, G L KellettAbstract:We have previously shown that the hypersensitivity of KB MDR Cells to 2-deoxy-D-glucose is associated with diminished plasma membrane GLUT-1 levels compared with parental, non-MDR Cells. Here we report that MDR Cells are hypersensitive to the N-linked glycosylation inhibitor tunicamycin, which induces partial inhibition of GLUT-1 glycosylation and diminishes GLUT-1-mediated transport. The effect of tunicamycin, which also enhances the hypersensitivity of MDR Cells to 2-deoxy-D-glucose, could not be attributed to alterations in P-glycoprotein activity. The use of agents that act synergistically to diminish the level and activity of GLUT-1 in MDR Cells may be of clinical potential.