Chapter 18: Cell Organization and Movement II: Microtubules and Intermediate Filaments

Drugs Affecting Tubulin Polymerization Are Useful Experimentally and in Treatment of Diseases

The conserved nature of tubulins and their essential involvement in critical processes such as mitosis make them prime targets for both naturally occurring and synthetic drugs that affect polymerization or depolymerization. Historically, the first such drug was colchicine, present in extracts of the meadow saffron, which binds tubulin dimers so that they cannot polymerize into microtubules. Since most microtubules are in a dynamic state between dimers and polymers, the addition of colchicine sequesters all free dimers in the cytoplasm, resulting in loss of microtubules due to their natural turnover. Treatment of cultured cells with colchicine for a short time results in the depolymerization of all the cytoplasmic microtubules, leaving the more stable tubulin-containing centrosome (Figure 18-12a). When the colchicine is washed out to allow regrowth of the microtubules, they can be seen to grow from the centrosome, revealing its ability to nucleate the assembly of new microtubules (Figure 18-12b).

EXPERIMENTAL FIGURE 18-12 Microtubules grow from the MTOC. To investigate the assembly of microtubules in vivo, a cultured fibroblast was treated with colchicine until almost all the cytoplasmic microtubules were disassembled. The cell was then stained with antibodies to tubulin and viewed by immunofluorescence microscopy (a). The colchicine was then washed out to allow the reassembly of microtubules. Panel (b) shows the first stages of reassembly, revealing microtubules growing from the MTOC in the central region above the nucleus (dark areas). Note in panel (a) the remaining primary cilium (arrowhead; discussed in Section 18.5) associated with the centrosome, which is not depolymerized by colchicine treatment under these conditions. Note also the fluorescence from the cytoplasm, which is from unpolymerized αβ-tubulin dimers.

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Colchicine has been used for hundreds of years to relieve the joint pain of acute gout—a famous patient was King Henry VIII of England, who was treated with colchicine to relieve this ailment. A low level of colchicine relieves the inflammation caused in gout by reducing the microtubule dynamics of white blood cells, rendering them unable to migrate efficiently to the site of inflammation.

In addition to colchicine, a number of other drugs bind the tubulin dimer and restrain it from forming polymers. These drugs include podophyllotoxin (from juniper) and nocodazole (a synthetic drug).

Taxol, a plant alkaloid from the Pacific yew tree, binds microtubules and stabilizes them against depolymerization. Because taxol stops cells from dividing by inhibiting mitosis, it has been used to treat some cancers, such as those of the breast and ovary, where the cells are especially sensitive to the drug.