Selective, Covalent Modification of β -Tubulin Residue Cys-239 by T138067, an Antitumor Agent with in vivo Efficacy against Multidrug-Resistant Tumors
Microtubules are linear polymers of α - and β -tubulin heterodimers and are the major constituents of mitotic spindles, which are essential for the separation of chromosomes during mitosis. Here we describe a synthetic compound, 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067), whi...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1999-05, Vol.96 (10), p.5686-5691 |
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| creator | Shan, Bei Medina, Julio C. Santha, Edit Frankmoelle, Walter P. Ting-C. Chou Learned, Robert M. Narbut, Mathew R. Stott, Dean Wu, Pengguang Jaen, Juan C. Rosen, Terry Pieter B. M. W. M. Timmermans Beckmann, Holger |
| description | Microtubules are linear polymers of α - and β -tubulin heterodimers and are the major constituents of mitotic spindles, which are essential for the separation of chromosomes during mitosis. Here we describe a synthetic compound, 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067), which covalently and selectively modifies the β 1, β 2, and β 4 isotypes of β -tubulin at a conserved cysteine residue, thereby disrupting microtubule polymerization. Cells exposed to T138067 become altered in shape, indicating a collapse of the cytoskeleton, and show an increase in chromosomal ploidy. Subsequently, these cells undergo apoptosis. Furthermore, T138067 exhibits cytotoxicity against tumor cell lines that exhibit substantial resistance to vinblastine, paclitaxel, doxorubicin, and actinomycin D. T138067 is also equally efficacious in inhibiting the growth of sensitive and multidrug-resistant human tumor xenografts in athymic nude mice. These observations suggest that T138067 may be clinically useful for the treatment of multidrug-resistant tumors. |
| doi_str_mv | 10.1073/pnas.96.10.5686 |
| format | Article |
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Chou ; Learned, Robert M. ; Narbut, Mathew R. ; Stott, Dean ; Wu, Pengguang ; Jaen, Juan C. ; Rosen, Terry ; Pieter B. M. W. M. Timmermans ; Beckmann, Holger</creator><creatorcontrib>Shan, Bei ; Medina, Julio C. ; Santha, Edit ; Frankmoelle, Walter P. ; Ting-C. Chou ; Learned, Robert M. ; Narbut, Mathew R. ; Stott, Dean ; Wu, Pengguang ; Jaen, Juan C. ; Rosen, Terry ; Pieter B. M. W. M. Timmermans ; Beckmann, Holger</creatorcontrib><description>Microtubules are linear polymers of α - and β -tubulin heterodimers and are the major constituents of mitotic spindles, which are essential for the separation of chromosomes during mitosis. Here we describe a synthetic compound, 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067), which covalently and selectively modifies the β 1, β 2, and β 4 isotypes of β -tubulin at a conserved cysteine residue, thereby disrupting microtubule polymerization. Cells exposed to T138067 become altered in shape, indicating a collapse of the cytoskeleton, and show an increase in chromosomal ploidy. Subsequently, these cells undergo apoptosis. Furthermore, T138067 exhibits cytotoxicity against tumor cell lines that exhibit substantial resistance to vinblastine, paclitaxel, doxorubicin, and actinomycin D. T138067 is also equally efficacious in inhibiting the growth of sensitive and multidrug-resistant human tumor xenografts in athymic nude mice. 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Chou</creatorcontrib><creatorcontrib>Learned, Robert M.</creatorcontrib><creatorcontrib>Narbut, Mathew R.</creatorcontrib><creatorcontrib>Stott, Dean</creatorcontrib><creatorcontrib>Wu, Pengguang</creatorcontrib><creatorcontrib>Jaen, Juan C.</creatorcontrib><creatorcontrib>Rosen, Terry</creatorcontrib><creatorcontrib>Pieter B. M. W. M. Timmermans</creatorcontrib><creatorcontrib>Beckmann, Holger</creatorcontrib><title>Selective, Covalent Modification of β -Tubulin Residue Cys-239 by T138067, an Antitumor Agent with in vivo Efficacy against Multidrug-Resistant Tumors</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Microtubules are linear polymers of α - and β -tubulin heterodimers and are the major constituents of mitotic spindles, which are essential for the separation of chromosomes during mitosis. Here we describe a synthetic compound, 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067), which covalently and selectively modifies the β 1, β 2, and β 4 isotypes of β -tubulin at a conserved cysteine residue, thereby disrupting microtubule polymerization. Cells exposed to T138067 become altered in shape, indicating a collapse of the cytoskeleton, and show an increase in chromosomal ploidy. Subsequently, these cells undergo apoptosis. Furthermore, T138067 exhibits cytotoxicity against tumor cell lines that exhibit substantial resistance to vinblastine, paclitaxel, doxorubicin, and actinomycin D. T138067 is also equally efficacious in inhibiting the growth of sensitive and multidrug-resistant human tumor xenografts in athymic nude mice. These observations suggest that T138067 may be clinically useful for the treatment of multidrug-resistant tumors.</description><subject>Actinomycin</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>b-tubulin</subject><subject>Biological Sciences</subject><subject>Cell Cycle - drug effects</subject><subject>Cell growth</subject><subject>Cell lines</subject><subject>Cellular biology</subject><subject>Cysteine - chemistry</subject><subject>Cytoskeleton - drug effects</subject><subject>Diploidy</subject><subject>Drug resistance</subject><subject>Drug Resistance, Multiple</subject><subject>Heterologous transplantation</subject><subject>Humans</subject><subject>Isotypes</subject><subject>Leukemia, Lymphoid - drug therapy</subject><subject>Medical research</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Microtubules</subject><subject>Microtubules - metabolism</subject><subject>Molecular Structure</subject><subject>Neoplasm Transplantation</subject><subject>Paclitaxel - pharmacology</subject><subject>Polymerization</subject><subject>Protein Binding</subject><subject>Sulfonamides - chemical synthesis</subject><subject>Sulfonamides - pharmacology</subject><subject>Tubulin - chemistry</subject><subject>Tumor cell line</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><subject>Vinblastine - pharmacology</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkt2KEzEUx4Mobl29FryQ4IXe7HTzOZPA3pSyfsCKoL0PmZlMNyWd1Eky2ifxPXwQn8kMrWsVwatwOL_fPyfhAPAUozlGFb3c9TrMZZmLOS9FeQ_MMJK4KJlE98EMIVIVghF2Bh6FsEEISS7QQ3CGEcVCMj4D3z4ZZ5poR3MBl37UzvQRvvet7Wyjo_U99B388R0Wq1QnZ3v40QTbJgOX-1AQKmG9hytMBSqrC6h7uOijjWnrB7hYT1FfbLyFWRvt6OF1N6U2e6jX2vYhX5RctO2Q1sUUG6LOxmqyw2PwoNMumCfH8xysXl-vlm-Lmw9v3i0XN0XDCY4F0bXQRKIGY8NEKZjEgjS1pB1mtJZacMbrziAmtZGtZqhmiHaacVy3bUXoObg6xO5SvTVtk0cetFO7wW71sFdeW_Vnp7e3au1HRbAkOOsvj_rgPycTotra0BjndG98CqqUFeO8JP8FcUW5oIxm8MVf4Manoc9foAjClHEheYYuD1Az-BAG090NjJGa9kJNe6FkOdXTXmTj-ek7T_jDImTg1RGYzF_t3wmqS85F8zWeRP2bzMCzA7AJ0Q93BBO4EvQnaLrWZA</recordid><startdate>19990511</startdate><enddate>19990511</enddate><creator>Shan, Bei</creator><creator>Medina, Julio C.</creator><creator>Santha, Edit</creator><creator>Frankmoelle, Walter P.</creator><creator>Ting-C. 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Chou</au><au>Learned, Robert M.</au><au>Narbut, Mathew R.</au><au>Stott, Dean</au><au>Wu, Pengguang</au><au>Jaen, Juan C.</au><au>Rosen, Terry</au><au>Pieter B. M. W. M. Timmermans</au><au>Beckmann, Holger</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective, Covalent Modification of β -Tubulin Residue Cys-239 by T138067, an Antitumor Agent with in vivo Efficacy against Multidrug-Resistant Tumors</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1999-05-11</date><risdate>1999</risdate><volume>96</volume><issue>10</issue><spage>5686</spage><epage>5691</epage><pages>5686-5691</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Microtubules are linear polymers of α - and β -tubulin heterodimers and are the major constituents of mitotic spindles, which are essential for the separation of chromosomes during mitosis. Here we describe a synthetic compound, 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067), which covalently and selectively modifies the β 1, β 2, and β 4 isotypes of β -tubulin at a conserved cysteine residue, thereby disrupting microtubule polymerization. Cells exposed to T138067 become altered in shape, indicating a collapse of the cytoskeleton, and show an increase in chromosomal ploidy. Subsequently, these cells undergo apoptosis. Furthermore, T138067 exhibits cytotoxicity against tumor cell lines that exhibit substantial resistance to vinblastine, paclitaxel, doxorubicin, and actinomycin D. T138067 is also equally efficacious in inhibiting the growth of sensitive and multidrug-resistant human tumor xenografts in athymic nude mice. These observations suggest that T138067 may be clinically useful for the treatment of multidrug-resistant tumors.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>10318945</pmid><doi>10.1073/pnas.96.10.5686</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Actinomycin Animals Antineoplastic Agents - pharmacology Apoptosis - drug effects b-tubulin Biological Sciences Cell Cycle - drug effects Cell growth Cell lines Cellular biology Cysteine - chemistry Cytoskeleton - drug effects Diploidy Drug resistance Drug Resistance, Multiple Heterologous transplantation Humans Isotypes Leukemia, Lymphoid - drug therapy Medical research Mice Mice, Nude Microtubules Microtubules - metabolism Molecular Structure Neoplasm Transplantation Paclitaxel - pharmacology Polymerization Protein Binding Sulfonamides - chemical synthesis Sulfonamides - pharmacology Tubulin - chemistry Tumor cell line Tumor Cells, Cultured Tumors Vinblastine - pharmacology |
| title | Selective, Covalent Modification of β -Tubulin Residue Cys-239 by T138067, an Antitumor Agent with in vivo Efficacy against Multidrug-Resistant Tumors |
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