Tubulin assembly inhibition colchicines

The role of microtubules in secretion is more clearly defined. Colchicine and vinblastine inhibit secretion, even in cytochalasin-B-treated cells, and D2O (which promotes tubulin assembly) enhances secretion in cytochalasin-treated cells. Microtubules may also be necessary for the translocation of phagocytic vesicles from the neutrophil periphery into the central region of the cytoplasm. Drugs affecting microtubule assembly may inhibit particle-induced oxidase activation or else increase oxidase activation in response to soluble agents such as fMet-Leu-Phe. 

The interface between ct-tubulln and p tubulln monomers in dimeric tubulin contains a hlgh-afflnlty but reversible binding site for colchicine. Colchicine-bearing tubulin dimers, at concentrations much less than the concentration of free tubulin subunits, can add to the end of a growing microtubule. However, the presence of one or two colchicine-bearing tubulins at the end of a microtubule prevents the subsequent addition or loss of other tubulin subunits. Thus colchicine poisons the end of a microtubule and alters the steady-state balance between assembly and disassembly. As a result of this disruption of microtubule dynamics, mitosis Is Inhibited in cells treated with low concentrations of colchicine. 

Much attention has been paid to taxol s unique mode of action, thanks to the pioneering efforts of Susan Horwitz [83, 84]. Mitotic spindle poisons , including colchicine, the vinca alkdoids, podophyllotoxin, and maytansine, bind to soluble tubulin and inhibit microtubule polymerization. Horwitz showed that, unlike any knovra antimitotic, taxol promotes microtubule assembly and stabilizes these structures to depolymerization by CaCl2 or cold [83, 84]. Typical of other ascomycetes and deuteromycetes tested, most of the fungi in our study do not appear to be compromised by taxol below 10 m [85]. Are yew-associated endophytes equally insensitive to spindle poisons like colchicine ... 

In addition to Intranuclear effects, DES disrupts mitotic and meiotlc spindles resulting in errors in cell division (JJ2) it is believed that DES acts directly on tubulin within 10 minutes of exposure since DES inhibits the GTP-dependent self-assembly of tubulin (11) and inhibits colchicine binding (12) ihe effect of DES is similar to that of colchicine which also specifically binds to tubulin and prevents the formation of microtubules and spindles. 

Podophyllotoxin is an aryltetralin lignan which has been isoiated from severai plants of the Podophyllum species, it is a potent cytotoxic agent against various cancer celi iines, stopping the cell cycle in metaphase through the inhibition of microtubules assembly by binding the colchicine site of the tubulin [112]. Because of numerous side effects, podophyllotoxin cannot be used as a drug. 

In addition to the inhibition of MT polymerization, more properties are shared by vinca domain compounds. As a hallmark, they inhibit the tubulin GTPase activity linked to MT assembly [42] as well as that induced by colchicine (see [33] and... 

Vinca alkaloids (vincristine, vinblastine, vinorelbine) are derived from the periwinkle plant (Vinca rosea). These agents work by binding to tubulin at a site different than colchicine or paclitaxel. They block polymerization, which prevents the formation of the mitotic spindle, and are used as antineoplastic agents. Taxanes produce a stabilization of microtubules similar to colchicine, but by a different mechanism, and also halt cells in metaphase. Paclitaxel (taxol) is the taxane used clinically. It is derived from the bark of the pacific yew. Taxol disrupts several microtubule-based functions as completely as inhibitors of polymerization, emphasizing the importance of assembly/disassembly balance in microtubule function. Recently, it has been found that paclitaxel also binds to and inhibits the function of a protein called bcl-2, an inhibitor of one or more pathways involved in mediating apoptosis. PaclitaxeTs interference with this function promotes apoptosis in addition to its microtubule-related inhibition of cell division. 

Some of the earliest studies of microtubules employed several drugs that inhibit mitosis, a cell process that depends on microtubule assembly and disassembly. Two such drugs isolated from plants, colchicine and taxol, have proved to be very powerful tools for probing microtubule function, partly because they bind only to ap-tubulin or microtubules and not to other proteins and because their concentrations in cells can be easily controlled. 

---