Anticancer therapy with novel tubulin-interacting drugs

Kavallaris, Maria; Verrills, Nicole M.; Hill, Bridget T.

doi:10.1054/drup.2002.0230

Cited by 120 publications

(77 citation statements)

References 77 publications

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“…Thus, selectivity of adduction is governed by both the recipient nucleophile and the chemistry of the adducting electrophile. Likewise, Cys-239 in tubulin is preferentially alkylated by anticancer drugs, including the colchicines, Vinca alkaloids, rhizoxin/maytansine, and taxanes (Jordan et al, 1998;Shan et al, 1999;Kavallaris et al, 2001;Casini et al, 2002;Scozzafava et al, 2002), and carbonic anhydrase III, which contains five cysteine residues, is selectively alkylated at Cys-186 by acrylonitrile (Nerland et al, 2003). Cysteine thiols are clearly common targets of reactive electrophilic metabolites and endogenous electrophiles, including lipid-derived ␣,␤-unsaturated aldehydes, such as 4-hydroxynonenal (4-HNE) and 4-oxononenal, and reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

Protein Electrophile-Binding Motifs: Lysine-Rich Proteins Are Preferential Targets of Quinones

Labenski¹,

Fisher²,

Lo³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Quinones represent an important class of endogenous compounds such as neurotransmitters and coenzyme Q10, electrophilic xenobiotics, and environmental toxicants that have known reactivity based on their ability to redox cycle and generate oxidative stress, as well as to alkylate target proteins. It is likely that topological, chemical, and physical features combine to determine which proteins become targets for chemical adduction. Chemical-induced post-translational modification of certain critical proteins causes a change in structure/function that contributes to the toxicological response to chemical exposure. In this study, we have identified a number of proteins that are modified by quinone-thioethers after administration of 2-(glutathion-S-yl)HQ. Parallel one-dimensional gel electrophoresis was performed, and the Coomassie-stained gel was aligned with the corresponding Western blot, which was probed for adductions. Immunopositive bands were then subjected to trypsin digestion and analyzed via liquid chromatography/tandem mass spectrometry. The proteins that were subsequently identified contained a higher than average (9.7 versus 5.5%) lysine content and numerous stretches of lysine run-ons, which is a presumed electrophile binding motif. Approximately 50% of these proteins have also been identified as targets for electrophilic adduction by a diverse group of chemicals by other investigators, implying overlapping electrophile adductomes. By identifying a motif targeted by electrophiles it becomes possible to make predictions of proteins that may be targeted for adduction and possible sites on these proteins that are adducted. An understanding of proteins targeted for adduction is essential to unraveling the toxicity produced by these electrophiles.Proteins have long been recognized as being critical targets of chemicals that produce acute tissue toxicities and cancer. Moreover, the adverse effects of many drugs are frequently mediated via their metabolic activation to reactive electrophilic metabolites, which subsequently bind covalently to proteins. Such reactive metabolites usually have low electron density and react with molecular centers of high electron density (i.e., nucleophiles). Target proteins for adduction usually contain strong nucleophilic sites, including cysteine thiols, lysine amines, histidine imidazoles, and protein N-terminal amines, which are readily attacked by reactive species (Guengerich et al., 2001;Casini et al., 2002). Other proteins contain weaker nucleophilic sites, including methionine sulfur, arginine guanidinium, tyrosine phenols, serine and threonine hydroxyls, and aspartate and glutamate carboxyls.Attempts to identify protein targets of reactive electrophilic metabolites have been complicated because 1) proteins have tremendously diverse structures and properties, 2) unmodified proteins are frequently present in excess, and 3) radiolabeled chemicals of sufficiently high specific activity are often unavailable or prohibitively expensive. Antibody-based approaches to a...

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Section: Discussionmentioning

confidence: 99%

Protein Electrophile-Binding Motifs: Lysine-Rich Proteins Are Preferential Targets of Quinones

Labenski¹,

Fisher²,

Lo³

et al. 2009

Drug Metab Dispos

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“…A chemically diverse group of antimitotic drugs target microtubules and have been used with great success in the treatment of cancer (8). These can be broadly classified either as tubulin polymerizers (e.g., taxanes) or depolymerizers (the Vinca alkaloids, colchicines, and nocodazole).…”

Section: Introductionmentioning

confidence: 99%

The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

et al. 2009

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Pyrrolo-1,5-benzoxazepine-15 (PBOX-15) is a novel microtubule depolymerization agent that induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines. Chronic lymphocytic leukemia (CLL) is characterized by clonal expansion of predominately nonproliferating mature B cells. Here, we present data suggesting PBOX-15 is a potential therapeutic agent for CLL. We show activity of PBOX-15 in samples taken from a cohort of CLL patients (n = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (n = 19) in a dose-dependent manner, with mean IC 50 of 0.55 μmol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgV H genes, CD38 and zeta-associated protein 70 (ZAP-70) expression, and fludarabine-resistant cells with chromosomal deletions in 17p. In addition, PBOX-15 was more potent than fludarabine in inducing apoptosis in fludarabine-sensitive cells. Pharmacologic inhibition and small interfering RNA knockdown of caspase-8 significantly inhibited PBOX-15-induced apoptosis. Pharmacologic inhibition of c-jun NH 2 -terminal kinase inhibited PBOX-15-induced apoptosis in mutated IgV H and ZAP-70 −

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“…This has led to the search for novel microtubule-stabilizing agents lacking these limitations of taxanes (3,20).…”

Section: Introductionmentioning

confidence: 99%

Patupilone Acts as Radiosensitizing Agent in Multidrug-Resistant Cancer Cells In vitro and In vivo

Hofstetter

Vuong²,

Broggini-Tenzer³

et al. 2005

Clinical Cancer Research

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Interference with microtubule function is a promising antitumoral concept. Paclitaxel is a clinically validated tubulin-targeting agent; however, treatment with paclitaxel is often limited by taxane-related toxicities and is ineffective in tumors with multidrug-resistant cells. Patupilone (EPO906, epothilone B) is a novel non-taxane-related microtubule-stabilizing natural compound that retains full activity in multidrug-resistant tumors and is clinically less toxic than paclitaxel. Here we have investigated the effect of combined treatment with ionizing radiation and patupilone or paclitaxel in the P-glycoprotein-overexpressing, p53-mutated human colon adenocarcinoma cell line SW480 and in murine, genetically defined E1A/ras-transformed paclitaxel-sensitive embryo fibroblasts. Patupilone and paclitaxel alone and in combination with ionizing radiation reduced the proliferative activity of the E1A/ras-transformed cell line with similar potency in the sub and low nanomolar range. SW480 cells were only sensitive to patupilone, and combined treatment with low-dose patupilone (0.1 nmol/L) followed by clinically relevant doses of ionizing radiation (2 and 5 Gy) resulted in a supra-additive cytotoxic effect. Inhibition of the drug efflux protein P-glycoprotein with verapamil resensitized SW480 cells to treatment with low doses of paclitaxel alone and in combination with IR. In tumor xenografts derived from SW480 cells a minimal treatment regimen with patupilone and fractionated irradiation (1 Â 2 mg/kg plus 4 Â 3 Gy) resulted in an at least additive tumor response with extended tumor growth arrest. Analysis by flow cytometry in vitro revealed an apoptosis-and G 2 -M-independent mode of radiosensitization by patupilone. Interestingly though, a transient accumulation of cells in S phase was observed on combined treatment. Overall, patupilone might be a promising alternative in paclitaxel-resistant, P-glycoproteinoverexpressing tumors for a combined treatment regimen using ionizing radiation and a microtubule inhibitor.

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Anticancer therapy with novel tubulin-interacting drugs

Cited by 120 publications

References 77 publications

Protein Electrophile-Binding Motifs: Lysine-Rich Proteins Are Preferential Targets of Quinones

Protein Electrophile-Binding Motifs: Lysine-Rich Proteins Are Preferential Targets of Quinones

The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

Patupilone Acts as Radiosensitizing Agent in Multidrug-Resistant Cancer Cells In vitro and In vivo

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