TXR1-mediated thrombospondin repression: a novel mechanism of resistance to taxanes?

The usefulness of chemotherapeutic agents for the clinical treatment of cancer relies on their toxic effects on dividing cells. While most anti-cancer drugs directly affect DNA synthesis or integrity, the vinca-alkaloids and taxanes act by disrupting the cellular microtubule network (depicted schematically in Fig. 1; for review, see Zhou and Giannakakou 2005). In addition to providing structural integrity as part of the cytoskeleton, microtubules function as the cell’s freeway system by providing the infrastructure along which cargo can be transported by motor proteins such as kinesin and dynein. During cell division, microtubules are critically important for the formation of the mitotic spindle, which dictates the proper segregation of chromosomes during mitosis. Microtubules are synthesized through the polymerization of and -tubulin subunits on their fast-growing, or plus, ends. At the same time, they are degraded on their slow-growing, or minus, ends by the release of / dimers into the cytosol. The combined processes of assembly and disassembly cause microtubules to be in a state of “dynamic instability,” which allows the growing or shortening of individual microtubules as required. Anti-microtubule agents exert their anti-cancer effect by disrupting normal microtubule dynamics in distinct fashions. Whereas vinca-alkaloids are able to bind to free tubulin, thereby preventing microtubule assembly and concomitant mitotic spindle formation, they cannot associate with polymerized tubulin present in microtubules. In contrast, taxanes interact with polymerized tubulin to cause microtubule stabilization. As a result, cells become overloaded with microtubules and are unable to resolve the mitotic spindle, causing a mitotic arrest or apoptosis. Taxol, the prototype chemotherapeutic of the taxane family, was isolated in the early 1970s from Taxus brevifolia. In recent years, taxol/paclitaxel and taxotere/docetaxel, a semisynthetic taxane identified in the 1980s, have become part of standard drug treatment regimens and are widely used in the clinic to treat a variety of human malignancies, including breast, ovarian, lung, gastric, and prostate cancers. The latter two are of special interest because taxanes may prove to offer some advances in the treatment of these otherwise refractory diseases.