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...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1999-05, Vol.96 (10), p.5686-5691
Main Authors: 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
Format: Article
Language:English
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.96.10.5686