Spindle poisons

The chromatid separation process has also remained mysterious. It is an autonomous process that does not direcdy depend on the mitotic spindle (Wilson 1925, Mazia 1961). This is most vividly seen in cells whose spindles have been destroyed by spindle poisons such as colchicine. In many organisms, in particular in plant cells, the cell cycle delay induced by colchicine is only transient and chromatids eventually split apart in the complete absence of a mitotic spindle (Mole-Bajer 1958, Rieder Palazzo 1992) (Fig. 2). Mitosis in the presence of colchicine or colcemid (known as c-mitosis) leads to the production of daughter cells with twice the normal complement of chromosomes. This process is routinely used for manipulating plant genomes and may contribute to the therapeutic effects of taxol in treating breast cancer. 

Sbrana I, Di Sibio A, Lomi A, Scarcelli V (1993) C-mitosis and numerical chromosome aberration analyses in human-lymphocytes - 10 known or suspected spindle poisons. Mutat Res 287 57-70 Senesi N, Loffredo E, Padovano G (1990) Effects of humic acid-herbicide interactions on the growth of Pisum sativum in nutrient solution. Plant Soil 127 41-47... 

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. 

The contractile proteins of the spindle apparatus must draw apart the replicated chromosomes before the cell can divide. This process is prevented by the so-called spindle poisons (see also colchicine, p. 316) that arrest mitosis at metaphase by disrupting the assembly of microtubules into spindle threads. The vinca alkaloids, vincristine and vinblastine (from the periwinkle plant. Vinca rosea) exert such a cell-cycle-specific effect. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms. 

Kobayashi A, Hino T, Yata S, ItohTJ, Sato H, Kawazu K, Unique spindle poisons, curvularins and its derivatives, isolated from Penicillium species, Agric Biol Chem... 

Vinca dimer indole alkaloids (e.g. vinbiastine) act as spindle poisons. They bind tubulin, inhibiting polymerisation into microtubules, the major elements of the cytoskeleton [100]. Vinblastine itself and its analogue vinoreibine (Navelbine ) [101] are marketed for cancer therapies (Fig. 36). Vinflunine (Javlor ) is a member of second-generation Vinca dimer alkaloids. This 4 -difluoro analogue is more active than vinoreibine in several cancers (Fig. 36). It is now in phase III clinical... 

Vinca dimer indole alkaloids (e.g., vinblastine) act as spindle poison. They bind tubulin, inhibiting polymerization into microtubules, major elements of the cytoske-Vinblastine itself and its analogue vinorelbine (Navelbine ) are marketed for cancer therapies (Figure 4.48). Because of the obvious difficulty in synthesizing such highly complex structures, there were no reports on the preparation of fluorinated derivatives until the remarkable work of Jacquesy s group on the synthesis in super-acidic media. 5 ... 

These proteins form complexes with cdc20, thereby sequestering it from activating the APC/C complex (66) (Fig. 4). The spindle checkpoint is activated in response to various spindle poisons, such as nocodazole, a drug that depolymerizes microtubules and thus prevents the attachment of microtubules to the kinetochores. On the other hand, taxanes inhibit the dynamic instability of the spindle and allow microtubule attachment but prevent the generation of tension across kinetochores. 

Paclitaxel is an alkaloid ester derived from the Pacific yew (Taxus brevifolia) and the European yew (Taxus baccata). The drug functions as a mitotic spindle poison through high-affinity binding to microtubules with enhancement of tubulin polymerization. This promotion of microtubule assembly by paclitaxel occurs in the absence of microtubule-associated proteins and guanosine triphosphate and results in inhibition of mitosis and cell division. 

Colchicine is a specific spindle poison, which binds to tubulin, and inhibits its polymerization. Consequently, colchicine blocks mitosis, causing aneuploidy, the unequal partition of chromosomes, and metaphase arrest. 

Adler, I.-D., Kliesch, U., van Hiunmelen, P. Kirsch-Volders. M. (1991) Mouse micronucleus tests with known and suspect spindle poisons results from two laboratories. Mutagenesis, 6,47-53... 

Brunner, M., Albertini, S. Wtirgler, F.E. (1991) Effects of 10 known or suspected spindle poisons in the in vitro porcine brain tubulin assembly assay. Mutagenesis, 6, 65-70... 

Marrazzini, A., Betti, C., Bernacchi, F., Barrai, I. Barale, R. (1994b) Mieronueleus test and metaphase analyses in mice exposed to known and suspected spindle poisons. Mutagenesis, 9, 505-515... 

Xu, W. Adler, I.-D. (1990) Clastogenic effects of known and suspect spindle poisons studied by chromosome analysis in mouse bone marrow cells. Mutagenesis, 5, 371-374... 

K.I., Nishi, Y. Nakadate, M. (1996) Detection of in vitro clastogens and spindle poisons by... 

Sofuni, T., Honma. M.. Hayashi, M., Shimada, H., Tanaka, N., Wakuri, S., Awogi, T., Yamamoto, K.I., Nishi, Y. Nakadate, M. (1996) Detection of in vitro clastogens and spindle poisons by the mouse lymphoma assay using the microwell method interim report of an international collaborative study. Mutagenesis, 11, 349-355... 

Vincristine is also an alkaloid derivative of Vinca rosea and is closely related in structure to vinblastine. Its mechanism of action is considered to be identical to that of vinblastine in that it functions as a mitotic spindle poison leading to arrest of cells in the M phase of the cell cycle. Despite these similarities to vinblastine, vincristine has a strikingly different spectrum of clinical... 

Paclitaxel and docetaxel have been shown to act as spindle poisons, causing cell division cycle arrest, based on a unique mechanism of action.7-10 These drugs bind to the P-subunit of the tubulin heterodimer, the key constituent protein of cellular microtubules (spindles). The binding of these drugs accelerates the tubulin polymerization, but at the same time stabilizes the resultant microtubules, thereby inhibiting their depolymerization. The inhibition of microtubule depolymerization between the prophase and anaphase of mitosis results in the arrest of the cell division cycle, which eventually leads to the apoptosis of cancer cells. 

Many alkaloids are infamous for their strong toxicity towards animals and humans. Most of the deadly alkaloids fall into the class of neurotoxins (see above). The others have cytotoxic properties (Table 1.2). A cytotoxic effect can be generated when cell membranes are made leaky (as by saponins or steroidal alkaloids), or when elements of the cytoskeleton are inhibited. The spindle poisons vinblastine, vincristine, colchicine, and taxol are particularly famous. Actin filament formation is blocked by fungal poisons such as phalloidin from Amanita phalloides. 

Wink, M. (2007) Molecular modes of action of cytotoxic alkaloids - from DN A intercalation, spindle poisoning, topoisomerase inhibition to apoptosis and multiple drug resistance, in The Alkaloids (ed. G. CordeU), Vol. 64. Academic Press, San Diego,... 

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