Drugs Affecting Microtubules

Sliding of one microtubule along another in an intact cilium causes the cilium to bend, creating a power stroke. 

Microtubule systems are used in the cell for many other functions, such as transport of organelles and vesicles, and separating genetic material on the mitotic spindle and other motile events of the cell cycle. Substances that interfere with microtubule growth or turnover, or with microtubule interaction with motor proteins, will disrupt these 

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. 

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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. 

Stearns, T., M. A. Hoyt, and D. Botstein (1990). Yeast mutants sensitive to antimicrotubule drugs define three genes that affect microtubule function. Genetics 124, 251-262. 

Other drugs bind to different sites on tubulin dimers or to microtubules and therefore affect microtubule stability through different mechanisms. For example, at low concentrations, taxol binds to microtubules and stabilizes them by inhibiting their shortening. 

No. Both drugs disrupt microtubule assembly. However, thiabendazole appears to specifically depolymerize a sub-population of stable, acetylated microtubules, which are not affected by colchicine. 

Drug-drug interactions Imatinib Peripheral neuropathy is uncommon in imatinib-treated patients and has previously been reported only during combination therapy with cytotoxic agents that affect microtubule function, such as vinca alkaloids and taxanes. A suspected adverse interaction with amlodipine has been reported, with a temporal association between amlodipine and symptoms of imatinib toxicity [21 ]. 

There are several efflux pumps which may affect absorption, blood-brain-barrier penetration, and reabsorption from kidney microtubules. The most commonly tested efflux pump in early drug discovery is the P-glycoprotein. Assays to identify P-glycoprotein substrates or inhibitors can be run using a variety of cell lines. 

As noted earlier, microtubule elongation has been characterized largely with respect to the involvement of guanine nucleotides and the modes of drug inhibition of microtubule formation. There have also been a number of important studies on the influence of microtubule-associated proteins and solution variables on the kinetics and thermodynamics of microtubule self-assembly. Of these, the characterization of the so-called mitotic spindle poisons has been particularly complex because of the variety of agents and the diversity of systems studied. For this reason, we shall concentrate on the other factors affecting the elongation process. 

Other chemicals, which affect tubulin polymerization or spindle microtubule stability, are podophyllotoxin and the drugs, paclitaxel, benomyl, griseofulvin, nocodazole, and colecimid. 

The mitotic spindle is part of a larger intracellular skeleton (cytoskele-ton) that is essential for the internal movements occurring in the cytoplasm of all eukaryotic cells. The mitotic spindle consists of chromatin, and a system of microtubules composed of the protein tubulin. The mitotic spindle is essential for the equal partitioning of DNA into the two daughter cells formed when a eukaryotic cell divides. Several plant-derived substances used as anticancer drugs disrupt this process by affecting the equilibrium between the polymerized and depolymerized forms of the microtubules, thereby causing cytotoxicity. 

Many compounds that perturb the cellular cytoskeleton affect phagocytosis and macropinocytosis. Binding to actin filaments by the natural product cytochalasin D blocks both of these uptake mechanisms. Disruption of microtubules by the antimitotic agents colchicine and nocodazole inhibits macropinocytosis and affects some mechanisms of phagocytosis. The diuretic drug amiloride, which is an inhibitor of Na+/H+ antiporters, selectively blocks macropinocytosis. By activating protein kinase C, phorbol esters represent a class of small molecules that promote macropinocytosis. 

The work carried out on the mode of action of benzimidazole anthelmintics indicate that drugs of this class may exert their action either by inhibiting the energy metabolism and affecting glucose uptake or by inhibiting the polymerisation of tubulins to microtubules [5,232-235]. 

Drugs that disturb the assembly and disassembly of microtubules have been widely used to treat various diseases. Indeed, more than 2500 years ago, the ancient Egyptians treated heart problems with colchicine. Nowadays, this drug is used primarily in the treatment of gout and certain other diseases affecting the joints and skin. Other inhibitors of microtubule dynamics, including taxol, are effective anticancer agents and are used in the treatment of ovarian cancer. I... 

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