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Mechanisms of Resistance to Antineoplastic Drugs
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
Philip J. Vickers, Alan J. Townsend, Kenneth H. Cowan
Another example in which drug resistance may be traced to a defect in the intracellular activation of a drug is provided by the antimetabolite MTX. This drug normally undergoes conversion to a family of polyglutamate forms, in which one to five additional residues of glutamic acid are joined via -γ-carboxyl linkages to the terminal glutamate residue of MTX, as shown in Figure 3. MTX polyglutamates are synthesized by the enzyme folyl-polyglutamate synthetase (FPGS), which catalyzes the polyglutamylation of the natural folate cofactors.29-33 The polyglutamylation of MTX does not dramatically alter the interaction of the drug with its principal target site, dihydrofolate reductase (DHFR).34 However, in contrast to the monoglutamate form of the drug, polyglutamates are retained within cells for much longer periods of time.35,36 Thus, the conversion of MTX to its polyglutamate forms expands the intracellular antifolate pool over time and provides for high levels of intracellular enzyme inhibitors long after extracellular drug levels fall. In addition, MTX polyglutamates are potent inhibitors of other enzymes in addition to DHFR, including aminoimidazolecarbox-amide ribonucleotide transformylase,37 glycinamide ribonucleotide transformylase,38 and thymidylate synthase (Figure 4).39 Therefore, the formation of polyglutamate metabolites has a dramatic effect upon the overall efficacy of MTX.
Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Microtubules have an external diameter of 25 nm and a length varying from 250 nm to 25 µm. Their dynamic properties are based on their inherent structure and polarity, which is dependent upon the tubulin isoforms from which they derive. At present, six isoforms of tubulin are known within eukaryotic cells: alpha-(α), beta-(β), gamma-(γ), delta-(δ), epsilon-(ε), and zeta-(ζ) tubulins), with each isoform containing a number of subtypes. For example, the beta-(β) subtypes include TUBB, TUBB1, TUBB2A, TUBB2B, TUBB2C, TUBB3, TUBB4, TUBB4Q, TUBB6, and TUBB8. The alpha-(α) and beta-(β) isoforms form the structure of the polymeric form of tubulin which constitutes the microtubules, and γ-tubulin functions as a template for the correct assembly of microtubules. These isoforms, which each have a molecular weight of approximately 50 kDa, can be further modified by various post-translational modifications, including tyrosination and de-tyrosination, acetylation, polyglutamylation, polyglycylation, phosphorylation, and palmitoylation. Except for tubulin tyrosine ligase (the enzyme that adds a tyrosine to nonassembled α-tubulin), most of the modifying enzymes act preferentially on tubulin subunits that are already incorporated into microtubules. Post-translational modifications of tubulin subunits appear to mark sub-populations of microtubules, selectively affecting their functions. Although they are not directly involved in determining the dynamic properties of microtubules, modifications such as sequential tyrosination/de-tyrosination/acetylation correlate well with the half-life and spatial distribution of microtubules.
Molecular mechanisms governing axonal transport: a C. elegans perspective
Published in Journal of Neurogenetics, 2020
Amruta Vasudevan, Sandhya P. Koushika
Polyglutamylation of microtubules, regulated by a balance between the activities of the deglutamylase CCPP-1 and glutamylase TTLL-11 in C. elegans, has been shown to regulate microtubule doublet structure and stability, facilitate the recruitment of KLP-6 (a Kinesin-3 family motor) and limit the transport velocity of the anterograde motor OSM-3 (a homodimeric Kinesin-2 family motor) (O’Hagan et al., 2011). Absence of CCPP-1 has been shown to cause progressive deterioration of cilia, suggesting that polyglutamylation-mediated microtubule stability and supported cargo transport are necessary for the maintenance of cilia (O’Hagan et al., 2011; 2017; O’Hagan & Barr, 2012). The above studies suggest that microtubule PTMs in C. elegans neurons, like vertebrate neurons, play a direct role in microtubule assembly, stability, directing intracellular cargo transport, and maintaining neuronal structure and function, perhaps in part by facilitating the transport of neuronal cargo.
The role of microtubules in the regulation of epithelial junctions
Published in Tissue Barriers, 2018
Ekaterina Vasileva, Sandra Citi
Among different types of cytoskeletal polymers, microtubules (MTs), along with actin filaments, are the most evolutionarily conserved, since they are present in all eukaryotes, where they promote the generation of mechanical force and movement through kinesin and dynein (for MTs), and myosin (for actin filaments) motors, respectively. Although proteins similar to tubulin and actin are also found in prokaryotes, the associated protein motors appear to be missing.1 MTs are hollow cylindrical polymers of heterodimeric subunits made of α- and β-tubulin, and are typically made up of 13 parallel protofilaments.2 They are polarized, with plus ends, which are highly dynamic, undergoing either rapid polymerization or rapid depolymerization (catastrophe), and minus ends, which are typically either stabilized or acting as sites of depolymerization.3 Polymerizing MTs are nucleated and stabilized at their minus ends by the γ-tubulin ring complex (γ-TuRC). The γ-TuRC is the main structural unit of microtubule organizing centers (MTOCs), which are found both at centrosomes, and at non-centrosomal sites, such as the Golgi apparatus.4 Tubulins are targets for numerous types of post-translational modifications (PTMs) affecting their C-terminal sequences, including de-tyrosination, Δ2-tubulin generation, polyglutamylation, polyglycylation, and acetylation.5 The functional significance and mechanisms of tubulin PTMs have been investigated in neuronal cells, where PTMs regulate MTs organization and interactions with motors, but their role in epithelial cells is less clear.
Novel Glu-based pyrazolo[3,4-d]pyrimidine analogues: design, synthesis and biological evaluation as DHFR and TS dual inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Mater Mahnashi, Mohammed Merae Alshahrani, Amer Al Ali, Abdulaziz Asiri, Mahrous A. Abou-Salim
During the process of DNA synthesis, a significant number of endogenic forces can challenge, and cells harbour a series of pathways to disseminate genome integrity1. Dihydrofolate reductase (DHFR) and thymidylate synthetase (TS) are key enzymes in nucleic acid synthesis, and they have long been evidenced as a crucial target of cancer chemotherapy2,3. DHFR reduces dihydrofolate (DHF) to tetrahydrofolate (THF) using NADPH, while TS catalyses the de novo synthesis of deoxythymidine monophosphate (dTMP) from deoxyuridine monophosphate (dUMP) using 5,10-Methylene THF as a cofactor, and thus initiates DNA synthesis and cell proliferation2,3. Therefore, DHFR and TS inhibitors cause THF and dTMP deficiency, resulting in RNA and DNA synthesis interference and apoptosis4. However, the dose-limiting toxicities, low solubility, short plasma half-life, low specificity, rapid diffusion throughout the body, weak brain permeability unless at high doses (1–8 g/m2), low absorption and drug resistance development are the main drawbacks of the first-in-class DHFR and TS inhibitors3–5. A major mechanism of drug resistance by target cells to clinically useful classical antifolates (Figure 1) is based on their need for polyglutamylation via the enzyme folylpoly-gamma-glutamate synthetase (FPGS), which catalyses the addition of several equivalents of glutamic acid to the γ-carboxyl group in the side chain and hence prevents drug efflux from the cell6. Therefore, developing a novel antifolate class of low toxicity and tumour resistance remains one of the major challenges that incessantly attracts intense interest2,3,5,7–10.