Anthracenedione–methionine conjugates are novel topoisomerase II-targeting anticancer agents with favorable drug resistance profiles

Lee, Chieh-Hua; Hsieh, Ming-Shun; Hsin, Ling‐Wei; Chen, Hsiang-Chin; Lo, Su-Chi; Fan, Jia-Rong; Chen, Wanru; Chen, Hung-Wei; Chan, Nei-Li; Li, Tsai-Kun

doi:10.1016/j.bcp.2012.01.025

Cited by 12 publications

(7 citation statements)

References 34 publications

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“…A total of 100 units/ml penicillin, 100 μg/ml streptomycin and 2 mM glutamine in a 5% CO 2 incubator at 37°C. Comet assay was used to determine chromosome DNA breaks ( 29 ). Briefly, cells (2 × 10 5 ) were treated with etoposide or etoplatins for 1 h, then the cells were collected and re-suspended in 1 ml ice-cold 1× phosphate-buffered saline buffer.…”

Section: Methodsmentioning

confidence: 99%

Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry

Wang

Chen

et al. 2017

Nucleic Acids Research

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Human type II topoisomerase (Top2) isoforms, hTop2α and hTop2β, are targeted by some of the most successful anticancer drugs. These drugs induce Top2-mediated DNA cleavage to trigger cell-death pathways. The potency of these drugs correlates positively with their efficacy in stabilizing the enzyme-mediated DNA breaks. Structural analysis of hTop2α and hTop2β revealed the presence of methionine residues in the drug-binding pocket, we therefore tested whether a tighter Top2-drug association may be accomplished by introducing a methionine-reactive Pt2+ into a drug to further stabilize the DNA break. Herein, we synthesized an organoplatinum compound, etoplatin-N2β, by replacing the methionine-juxtaposing group of the drug etoposide with a cis-dichlorodiammineplatinum(II) moiety. Compared to etoposide, etoplatin-N2β more potently inhibits both human Top2s. While the DNA breaks arrested by etoposide can be rejoined, those captured by etoplatin-N2β are practically irreversible. Crystallographic analyses of hTop2β complexed with DNA and etoplatin-N2β demonstrate coordinate bond formation between Pt2+ and a flanking methionine. Notably, this stable coordinate tether can be loosened by disrupting the structural integrity of drug-binding pocket, suggesting that Pt2+ coordination chemistry may allow for the development of potent inhibitors with protein conformation-dependent reversibility. This approach may be exploited to achieve isoform-specific targeting of human Top2s.

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Section: Methodsmentioning

confidence: 99%

Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry

Wang

Chen

et al. 2017

Nucleic Acids Research

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“…Except for a difference between ring A-mediated interactions and minor adjustments of the nearby protein moieties, these two anthracenedione-stabilized structures are essentially indistinguishable, indicating that a loss of 1- and 4-hydroxyl groups compromises drug function mainly by reducing the number of drug–protein contacts. Additionally, interactions between the hydroxylalkylamino arms and the protein address why modifications of these two branching moieties affect drug efficacy (Figure 5C and Supplementary Figure S5C) (34). Taken together, these findings indicate that the new structures are pharmacologically relevant and that the reported ligand-replacement procedure for the structural characterization of drug-stabilized Top2cc may benefit the structure-based development of new Top2-targeting drugs.…”

Section: Resultsmentioning

confidence: 99%

On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs

Ying-Ren

et al. 2013

Nucleic Acids Research

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Type II topoisomerases (Top2s) alter DNA topology via the formation of an enzyme–DNA adduct termed cleavage complex, which harbors a transient double-strand break in one DNA to allow the passage of another. Agents targeting human Top2s are clinically active anticancer drugs whose trapping of Top2-mediated DNA breakage effectively induces genome fragmentation and cell death. To understand the structural basis of this drug action, we previously determined the structure of human Top2 β-isoform forming a cleavage complex with the drug etoposide and DNA, and described the insertion of drug into DNA cleavage site and drug-induced decoupling of catalytic groups. By developing a post-crystallization drug replacement procedure that simplifies structural characterization of drug-stabilized cleavage complexes, we have extended the analysis toward other structurally distinct drugs, m-AMSA and mitoxantrone. Besides the expected drug intercalation, a switch in ribose puckering in the 3′-nucleotide of the cleavage site was robustly observed in the new structures, representing a new mechanism for trapping the Top2 cleavage complex. Analysis of drug-binding modes and the conformational landscapes of the drug-binding pockets provide rationalization of the drugs’ structural-activity relationships and explain why Top2 mutants exhibit differential effects toward each drug. Drug design guidelines were proposed to facilitate the development of isoform-specific Top2-targeting anticancer agents.

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“…Furthermore, in another study from the same research group, 1,4-bis-L/lmethionine-conjugated MTX-induced DNA breaks, cancer cell apoptosis, and revealed antitumor activities comparable to those of MTX. At the same time, the conjugated drug showed more favorable drug resistance profiles and a higher maximum tolerated dose in mice, indicating less toxicity (Lee et al 2012).…”

Section: Topoisomerase Inhibitionmentioning

confidence: 89%

Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone

et al. 2016

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Anthracyclines, e.g., doxorubicin (DOX), and anthracenediones, e.g., mitoxantrone (MTX), are drugs used in the chemotherapy of several cancer types, including solid and non-solid malignancies such as breast cancer, leukemia, lymphomas, and sarcomas. Although they are effective in tumor therapy, treatment with these two drugs may lead to side effects such as arrhythmia and heart failure. At the same clinically equivalent dose, MTX causes slightly reduced cardiotoxicity compared with DOX. These drugs interact with iron to generate reactive oxygen species (ROS), target topoisomerase 2 (Top2), and impair mitochondria. These are some of the mechanisms through which these drugs induce late cardiomyopathy. In this review, we compare the cardiotoxicities of these two chemotherapeutic drugs, DOX and MTX. As described here, even though they share similarities in their modes of toxicant action, DOX and MTX seem to differ in a key aspect. DOX is a more redox-interfering drug, while MTX induces energy imbalance. In addition, DOX toxicity can be explained by underlying mechanisms that include targeting of Top2 beta, mitochondrial impairment, and increases in ROS generation. These modes of action have not yet been demonstrated for MTX, and this knowledge gap needs to be filled.

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Anthracenedione–methionine conjugates are novel topoisomerase II-targeting anticancer agents with favorable drug resistance profiles

Cited by 12 publications

References 34 publications

Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry

Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry

On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs

Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone

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