Paclitaxel microtubule blocking

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. 

The more recently discovered Taxol (paclitaxel) was extracted from the bark of the Pacific yew.f It stabilizes microtubules, inhibiting their disassembly.s Taxol also blocks mitosis and causes the cells which fail to complete mitosis to die. Taxol has been syn-thesizedf and is a promising drug that is being used... 

Vinblastine (6.73) is an antimitotic drug that prevents polymerization of tubulin (Figure 6.26). When incubated with tubulin, vinblastine complexes in a 1 1 ratio with tubulin proteins. By blocking polymerization, vinblastine prevents microtubule formation and therefore mitosis. In contrast, paclitaxel (Taxol, 6.74) and epothilone B (6.75) stabilize aggregated tubulin. As a result, in the presence of paclitaxel and epothilone B, cells form static bundles of microtubules that are nonfunctional. Vinblastine and paclitaxel are both approved for clinical use against cancer. Ixabepilone (6.76), an analogue of epothilone B (6.75), has been approved by the FDA for treatment of certain forms of breast cancer. The European Medicines Agency (EMEA) did not approve ixabepilone out of concern over severe side effects.27... 

Fig. 3 a Model for the binding of cyclostreptin at the proposed initial MSA binding site at pore type I. Taken from [21]. b Scheme of the route of paclitaxel to its lumenal site in the microtubules. Paclitaxel binds to the external site at the pores of the microtubules, being later transported to its lumenal site while the external site gets blocked. In the presence of cyclostreptin the external site gets irreversibly blocked thus, paclitaxel cannot reach the lumenal site... 

Microtubule dynamics alterations also showed impacts on resistance. Goncalves et al. found a 57% increase of microtubule instability in paclitaxel-resistant cell A549-T12 as compared with parental sensitive cell A549, and a 167% overall increase in the more resistant cell A549-T24. ° It is interesting to note that the resistant cells, in the absence of paclitaxel, suffered mitotic block as well, which suggests that both increased or suppressed microtubule dynamics can impair cell function and proliferation. 

Most of the important antitumor compounds used for chemotherapy of tumors are microbially-produced antibiotics. These include actinomycin D, mitomycin, bleomycins and the anthracyclines, daunorubicin and doxorubicin. The recent successful molecule, taxol (=paclitaxel), was discovered in plants but also is a fungal metabolite. It is approved for breast and ovarian cancer and is the only antitumor drug known to act by blocking depolymerization of microtubules. In addition, taxol promotes tubulin polymerization and inhibits rapidly dividing mammalian cancer cells. It also inhibits fungi such as Pythium, Phytopthora and Aphanomyces spp. by the same mechanism. ... 

The plant alkaloids (vincristine, vinblastine, vindesine and vinorelbine) and taxoids (paclitaxel, docetaxel) inhibit microtubule assembly and cause cell cycle arrest in mitosis. They particularly cause bone marrow depression, peripheral neuropathy (vincristine) and alopecia. Etoposide blocks the cell cycle before mitosis. 

Paclitaxel acts by enhancing microtubule assembly and stabilizing microtubules (1,2). Microtubules consist of polymers of tubulin in dynamic equilibrium with tubulin heterodimers. Their principal function is the formation of the mitotic spindle during cell division, but they are also active in many interphase functions, such as cellular motility, intracellular transport, and signal transmission. Paclitaxel inhibits the depolymerization of tubulin, and the microtubules formed in the presence of paclitaxel are extremely stable and dysfunctional. This stabilization impairs the essential assembly and disassembly required for dynamic cellular processes, and death of the cell results through disruption of the normal microtubular dynamics required for interphase processes and cell division. In tumor cells, cytotoxicity is represented by the appearance of abnormal microtubular bundles, which accumulate during G2 and mitosis, blocking the cell cycle (3). 

The mechanism of action of the vinca alkaloids is that of the inhibition of the polymerization of tubulin to microtubules. The cellular protein tubulin, which occurs in a- and /3-forms, is essential for proper cellular function. During mitosis tubulin polymerizes to form microtubules, which are long tube-shaped protein polymers. The equilibrium between unpolymerized a- and /3-tubulin and microtubules is an important one and any disruption of this equilibrium can send dividing cells into mitotic block and apoptosis. The vinca alkaloids bind to /3-tubulin at a different site from paclitaxel (Taxol) and act to prevent tubulin assembly. 

The taxanes originally were extracted from the bark of the Pacific Yew tree and have found widespread use as anticancer agents. The structurally related taxanes, docetaxel and pacUtaxel, bind to and stabilize polymerized microtubules. Cells that enter mitosis in the presence of paclitaxel attempt to assemble a spindle apparatus, however the inhibition of depolymerization renders this structure unable to properly position chromosomes at the metaphase plate. Therefore, although kinetochores bind to microtubules, there is insufficient tension to inactivate the SAC. Paclitaxel-treated cells become blocked in mitosis, and eventually die by the mechanisms just described. Currently, there... 

Paclitaxel binds specifically to /3-tubulin and antagonizes the disassembly of microtubules bundles of microtubules and aberrant structures derived from microtubules appear in the M phase of the cell cycle, causing mitotic arrest. Cell kilhng is dependent on both drug concentration and duration of cell exposure. Drugs that block cell cycle progression prior to mitosis antagonize the toxic effects of taxanes. 

Poland TB, Dentler WL, Suprenant KA, Gupta ML, Himes RH (2005) Paclitaxel-induced microtubule stabilizatimi causes mitotic block and apoptotic-like cell death in a pacUtaxel-sensitive strain of Saccharomyces cerevisiae. Yeast 22 971-978. doi 10.1002/yea.l284... 

Because microtubules do not disassemble in the presence of docetaxel, they accumulate inside the cell and cause initiation of apoptosis. Apoptosis is also encouraged by the blocking of apoptosis-blocking bcl-2 oncoprotein. Both in vitro and in vivo analyses show that antineoplastic activity of docetaxel against a wide range of known cancer cells would be greater than paclitaxel, possibly due to its more rapid intracellular uptake. 

Paclitaxel/taxol Increases ceramide levels, targets microtubules, interferes with tubulin dynamics and blocks mitosis Crossin and Camey, 1981... 

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