Interaction of the tumor inhibitor IKP-104, a 4(1H)-pyridinone derivative, with microtubule proteins.
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| Abstract |
The effects of a mitotic arrestant, IKP-104, which has an antitumor activity, on the in vitro polymerization and depolymerization of rat brain microtubules were investigated. IKP-104 inhibited microtubule polymerization at concentrations greater than 0.71 x 10(-6) M, and its IC50 value was determined to be 1.31 x 10(-6) M by probit analysis. Fifty-two percent of pre-polymerized microtubules depolymerized at 1.31 x 10(-6) M IKP-104. Electron micrographs of microtubules taken immediately after treatment with 1 x 10(-3) M IKP-104 revealed a fraying of microtubule ends into elongated coil-like filaments, which were composed of 2 or 3 protofilaments. When microtubule protein treated with 1 x 10(-3) M IKP-104 was cleaved by trypsin, fragments of 41, 36, 34, 23, 21, 19 and 16 kilodaltons (kDa) derived from alpha-tubulin were produced. In particular, the 19, 23, and 34 kDa fragments were characteristically observed in the trypsin cleavage of microtubules tested with IKP-104, and these fragments were not observed with untreated microtubules. The effects of IKP-104 on microtubule protein mentioned above were mostly similar to those of vinblastine (VLB) and we suggest that IKP-104 bound to the site or sites near "VLB-binding site or sites" of alpha-tubulin subunit, resulting in induction of conformational changes.
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| Authors | F Mizuhashi, K Murata, T Kitagaki, I Tomita |
| Journal | Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 83 Issue 2 Pg. 211-8 (Feb 1992) ISSN: 0910-5050 [Print] Japan |
| PMID | 1556002 (Publication Type: Comparative Study, Journal Article) |
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