Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle.
TL;DR: This review describes the biochemistry of tubulin, microtubules, and the mitotic spindle and describes the natural and synthetic agents which are known to interact with tubulin.
Abstract: Tubulin is the biochemical target for several clinically used anticancer drugs, including paclitaxel and the vinca alkaloids vincristine and vinblastine. This review describes both the natural and synthetic agents which are known to interact with tubulin. Syntheses of the more complex agents are referenced and the potential clinical use of the compounds is discussed. This review describes the biochemistry of tubulin, microtubules, and the mitotic spindle. The agents are discussed in relation to the type of binding site on the protein with which they interact. These are the colchicine, vinca alkaloid, rhizoxin/maytansine, and tubulin sulfhydryl binding sites. Also included are the agents which either bind at other sites or unknown sites on tubulin. The literature is reviewed up to October 1997. © 1998 John Wiley & Sons, Inc., Med Res Rev, 18, No. 4, 259–296, 1998.
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TL;DR: Phylogenetic analysis of bacterial HDAC relatives suggests that all three HDAC classes precede the evolution of histone proteins and raises the possibility that the primary activity of some "histone deacetylase" enzymes is directed against non-histone substrates.
1,342 citations
TL;DR: This review highlights recent developments in the synthesis of functionalized 3,4-dihydropyrimidin-2(1H)-ones with a focus on the DHPMs recently developed as calcium channel modulators, alpha(1a) adrenoceptor-selective antagonists and compounds that target the mitotic machinery.
1,191 citations
TL;DR: The recent high-resolution analysis of the structure of tubulin and the microtubule has brought new insight to the study of microtubules function and regulation, as well as the mode of action of antimitotic drugs that disrupt normal micro Tubulin behavior.
Abstract: ▪ Abstract Microtubules are polymers that are essential for, among other functions, cell transport and cell division in all eukaryotes. The regulation of the microtubule system includes transcription of different tubulin isotypes, folding of α/β-tubulin heterodimers, post-translation modification of tubulin, and nucleotide-based microtubule dynamics, as well as interaction with numerous microtubule-associated proteins that are themselves regulated. The result is the precise temporal and spatial pattern of microtubules that is observed throughout the cell cycle. The recent high-resolution analysis of the structure of tubulin and the microtubule has brought new insight to the study of microtubule function and regulation, as well as the mode of action of antimitotic drugs that disrupt normal microtubule behavior. The combination of structural, genetic, biochemical, and biophysical data should soon give us a fuller understanding of the exquisite details in the regulation of the microtubule cytoskeleton.
771 citations
TL;DR: The present review will concentrate primarily on the medicinal chemistry of one of these drugs, combretastatin A4 (CA-4 a), which has been brought forward into the drug pipeline that share this mechanism of action.
Abstract: A growing solid tumor relies on a developing vasculature to meet its needs in terms of oxygen, nutrients, depuration, etc. This implies that if the vascular bed that has developed within the tumoral mass can be made to collapse, tumoral growth can be significantly hampered. Indeed, the first proof of principle that this could be achieved was provided more than 10 years ago when a ricin-conjugated antibody directed against an endothelial protein was able to eradicate the tumoral mass in mice.1-4 Therapeutically, two pharmacological strategies can be foreseen that stand on this observation: (1) the development of the growing tumoral vasculature can be arrested by drugs; (2) the established vasculature perfusing the tumoral mass can be destroyed by drugs. Among the crucial questions in the field is how to specifically target the endothelial cells participating in the tumoral neovasculature without causing damage to vasculature elsewhere. A wide body of data has emerged over this issue. 3 It has now been shown that the developing vasculature and the tumoral vasculature express unique proteins and that this uniqueness can be used for selective pharmacological targeting. Indeed, if we consider a plasma membrane protein expressed solely on the undesired vasculature, we could envisage the use of specific antibodies conjugated with toxins, vaccines, etc.3 Yet it is also possible that the neovasculature is more sensitive over normal tissues to more traditional small-molecule drugs. Indeed, this strategy has also been exploited, and a number of compounds have entered or are entering clinical trials (these drugs are cumulatively referred to as low molecular weight vasculature-disrupting agents). 4 For example, the growth of the neovasculature is dependent on activation of the vascular endothelial growth factor receptor, and therefore, a number of receptor antagonists have been devised and are currently tested or employed. 5 Disruption of tubulin polymerization also disrupts the formation of tumoral vasculature, and it is therefore no surprise that a number of agents have been brought forward into the drug pipeline that share this mechanism of action. The present review will concentrate primarily on the medicinal chemistry of one of these drugs, combretastatin A4 (CA-4 a
575 citations
TL;DR: It is shown that rhizoxin is not biosynthesized by the fungus itself, but by endosymbiotic, that is, intracellular living, bacteria of the genus Burkholderia, which extends the fungus–plant interaction to a third, bacterial, key-player, and opens new perspectives for pest control.
Abstract: The antitumour agent rhizoxin is a fungal metabolite produced by Rhizopus microsporus, the pathogen that causes one of the most destructive diseases of rice crops, rice seedling blight. Or so we thought. Now it has been discovered that Rhizopus is not the true producer of rhizoxin. In fact it is synthesized by a bacterium of the genus Burkholderia, living in the fungus as an endosymbiont. Rhizoxin causes cell-cycle arrest in the plant cells, and the fungal pathogen and its symbiont both benefit from the decaying plant matter produced. A number of plant pathogenic fungi belonging to the genus Rhizopus are infamous for causing rice seedling blight. This plant disease is typically initiated by an abnormal swelling of the seedling roots without any sign of infection by the pathogen1,2,3,4. This characteristic symptom is in fact caused by the macrocyclic polyketide metabolite rhizoxin that has been isolated from cultures of Rhizopus sp.5,6. The phytotoxin exerts its destructive effect by binding to rice β-tubulin, which results in inhibition of mitosis and cell cycle arrest7,8. Owing to its remarkably strong antimitotic activity in most eukaryotic cells, including various human cancer cell lines, rhizoxin has attracted considerable interest as a potential antitumour drug9,10. Here we show that rhizoxin is not biosynthesized by the fungus itself, but by endosymbiotic, that is, intracellular living, bacteria of the genus Burkholderia. Our unexpected findings unveil a remarkably complex symbiotic-pathogenic relationship that extends the fungus–plant interaction to a third, bacterial, key-player, and opens new perspectives for pest control.
554 citations
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TL;DR: It is reported here that taxol acts as a promoter of calf brain microtubule assembly in vitro, in contrast to plant products such as colchicine and podophyllotoxin, which inhibit assembly.
Abstract: TAXOL (Fig. 1) was isolated from the plant Taxus brevifolia (western yew) by Wani et al., who reported that the molecule has antitumour activity in several experimental systems1. In our laboratory we have found that taxol, a low molecular weight neutral compound, completely inhibits division of exponentially growing HeLa cells at low concentrations of drug (0.25 µM) that have no significant effects on DNA, RNA or protein synthesis during a 4-h incubation with the cells. HeLa cells incubated with taxol for 20 h are blocked in late G2 and/or M (ref. 2). We report here that taxol acts as a promoter of calf brain microtubule assembly in vitro, in contrast to plant products such as colchicine and podophyllotoxin, which inhibit assembly. Taxol decreases the lag time for microtubule assembly and shifts the equilibrium for assembly in favour of the microtubule, thereby decreasing the critical concentration of tubulin required for assembly. Microtubules polymerised in the presence of taxol are resistant to depolymerisation by cold (4 °C) and CaCl2 (4 mM).
3,430 citations
TL;DR: It is reported here that angiogenic activity first appears in a subset of hyperplastic islets before the onset of tumour formation, suggesting that induction of angiogenesis is an important step in carcinogenesis.
Abstract: It is now well established that unrestricted growth of tumours is dependent upon angiogenesis. Previous studies on tumour growth, however, have not revealed when or how the transition to an angiogenic state occurs during early tumour development. The advent of transgenic mice carrying oncogenes that reproducibly elicit tumours of specific cell types is providing a new format for studying multi-step tumorigenesis. In one of these models, transgenic mice expressing an oncogene in the beta-cells of the pancreatic islets heritably recapitulate a progression from normality to hyperplasia to neoplasia. We report here that angiogenic activity first appears in a subset of hyperplastic islets before the onset of tumour formation. A novel in vitro assay confirms that hyperplasia per se does not obligate angiogenesis. Rather, a few hyperplastic islets become angiogenic in vitro at a time when such islets are neovascularized in vivo and at a frequency that correlates closely with subsequent tumour incidence. These findings suggest that induction of angiogenesis is an important step in carcinogenesis.
1,995 citations
1,940 citations
Journal Article•
TL;DR: Epothilones represent a novel structural class of compounds, the first to be described since the original discovery ofTaxol, which not only mimic the biological effects of taxol but also appear to bind to the same microtubule-binding site as taxol.
Abstract: Tubulin polymerization into microtubules is a dynamic process, with the equilibrium between growth and shrinkage being essential for many cellular processes. The antineoplastic agent taxol hyperstabilizes polymerized microtubules, leading to mitotic arrest and cytotoxicity in proliferating cells. Using a sensitive filtration-calorimetric assay to detect microtubule nucleating activity, we have identified epothilones A and B as compounds that possess all the biological effects of taxol both in vitro and in cultured cells. The epothilones are equipotent and exhibit kinetics similar to taxol in inducing tubulin polymerization into microtubules in vitro (filtration, light scattering, sedimentation, and electron microscopy) and in producing enhanced microtubule stability and bundling in cultured cells. Furthermore, these 16-membered macrolides are competitive inhibitors of [3H]taxol binding, exhibiting a 50% inhibitory concentration almost identical to that of taxol in displacement competition assays. Epothilones also cause cell cycle arrest at the G2-M transition leading to cytotoxicity, similar to taxol. In contrast to taxol, epothilones retain a much greater toxicity against P-glycoprotein-expressing multiple drug resistant cells. Epothilones, therefore, represent a novel structural class of compounds, the first to be described since the original discovery of taxol, which not only mimic the biological effects of taxol but also appear to bind to the same microtubule-binding site as taxol.
1,188 citations
TL;DR: The total synthesis of taxol is reported by a convergent strategy, which opens a chemical pathway for the production of both the natural product itself and a variety of designed taxoids.
Abstract: Taxol, a substance originally isolated from the Pacific yew tree (Taxus brevifolia) more than two decades ago, has recently been approved for the clinical treatment of cancer patients. Hailed as having provided one of the most significant advances in cancer therapy, this molecule exerts its anticancer activity by inhibiting mitosis through enhancement of the polymerization of tubulin and consequent stabilization of microtubules. The scarcity of taxol and the ecological impact of harvesting it have prompted extension searches for alternative sources including semisynthesis, cellular culture production and chemical synthesis. The latter has been attempted for almost two decades, but these attempts have been thwarted by the magnitude of the synthetic challenge. Here we report the total synthesis of taxol by a convergent strategy, which opens a chemical pathway for the production of both the natural product itself and a variety of designed taxoids.
976 citations