Selective, covalent modification of β-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors Journal Article
| Authors: | Shan, B.; Medina, J. C.; Santha, E.; Frankmoelle, W. P.; Chou, T. C.; Learned, R. M.; Narbut, M. R.; Stott, D.; Wu, P.; Jaen, J. C.; Rosen, T.; Timmermans, P. B. M. W. M.; Beckmann, H. |
| Article Title: | Selective, covalent modification of β-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors |
| 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 β1, β2, and β4 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. |
| Keywords: | controlled study; unclassified drug; human cell; doxorubicin; nonhuman; antineoplastic agents; paclitaxel; antineoplastic agent; animals; mice; cell cycle; apoptosis; beta tubulin; animal experiment; animal model; protein binding; antineoplastic activity; tumor cells, cultured; vinblastine; animalia; mus musculus; cancer resistance; mice, nude; sulfonamides; rat; dactinomycin; microtubule assembly; molecular structure; neoplasm transplantation; drug binding site; tubulin; cell strain mcf 7; microtubule; microtubules; cytoskeleton; multidrug resistance; cysteine; colchicine; drug resistance, multiple; intraperitoneal drug administration; leukemia, lymphocytic; humans; human; male; priority journal; article; 2 fluoro 1 methoxy 4 pentafluorophenylsulfonamidobenzene; t 138067 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 96 |
| Issue: | 10 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 1999-05-01 |
| Start Page: | 5686 |
| End Page: | 5691 |
| Language: | English |
| DOI: | 10.1073/pnas.96.10.5686 |
| PUBMED: | 10318945 |
| PROVIDER: | scopus |
| PMCID: | PMC21921 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 16 August 2016 -- Source: Scopus |
