Mitoxantrone and ametantrone induce interstrand cross-links in DNA of tumour cells

Składanowski, Andrzej; Konopa, Jerzy

doi:10.1054/bjoc.1999.1095

Cited by 36 publications

(19 citation statements)

References 15 publications

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“…However, in addition to this mechanism it has also been demonstrated that the oxidation products of mitoxantrone (catalyzed by horseradish peroxidase) form a covalent complex with DNA in vitro (5), and similar drug-DNA adducts were subsequently also detected when mitoxantrone was oxidized in vitro by the human enzyme myeloperoxidase (6). The detection of drug-DNA adducts in mitoxantrone-treated promyelocytic HL-60 cells (which contain myeloperoxidase) (7) and in other tumor cells (8) subsequently provided direct support for the notion that mitoxantrone-DNA adducts may contribute to the mechanism of action of mitoxantrone.…”

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confidence: 99%

A Molecular Understanding of Mitoxantrone-DNA Adduct Formation

Parker

Buley

Evison

et al. 2004

Journal of Biological Chemistry

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When mitoxantrone is activated by formaldehyde it can form adducts with DNA. These occur preferentially at CpG and CpA sequences and are enhanced 2-3-fold at methylated CpG sequences compared with non-methylated sites. We sought to understand the molecular factors involved in enhanced adduct formation at these methylated sites. This required, first, clarification of factors that contributed to the formation of adducts at CpG sites. For this purpose mass spectrometry of an oligonucleotide duplex (containing a single CpG adduct site) was used to confirm the presence of an additional carbon atom (derived from formaldehyde) on the drug-DNA complex. The effect of 3-flanking sequences was revealed by electrophoretic analysis of oligonucleotidedrug adducts, and the preferred adduct-forming site was identified as 5-CGG-3. Radiolabeled studies of drug-DNA adducts confirmed that the site of attachment involved the exocyclic amino of guanine. Molecular modeling analysis of the relative stability of the intercalated form of mitoxantrone was consistent with observed adduct-forming potential of CG sites with varying flanking sequences. The known preference for adduct formation at methylated CG sites was confirmed by energetics calculations and shown to be due to a shift of equilibrium of the intercalated form of the drug from the major groove (at CG sites) to the minor groove (at methylated CG sites). This increases the relative amount of drug that is located adjacent to the N-2 exocyclic amino of guanine in the minor groove, where covalent linkage is facilitated. These results account for the enhanced covalent binding of mitoxantrone to methylated CG sequences and provide a molecular model of the interactions.

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confidence: 99%

A Molecular Understanding of Mitoxantrone-DNA Adduct Formation

Parker

Buley

Evison

et al. 2004

Journal of Biological Chemistry

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“…33 Reports indicated that MTX produce DNA cross-links and DNA replication defects in tumour cells, once DNA damage occurs, ATM pathway for HR repair is activated. 34 the maintenance of genomic integrity and cellular viability. 35 It is demonstrated that DNA-damaging drugs (including MTX) can trigger an ATM-dependent DNA damage response, leading to increased cytokine secretion and resistance to chemotherapy-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of differentially expressed genes and pathways associated with mitoxantrone treatment prostate cancer

et al. 2018

J Cellular Molecular Medi

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The global physiological function of specifically expressed genes of mitoxantrone (MTX)‐resistant prostate cancer (PCa) is unclear. In this study, gene expression pattern from microarray data was investigated for identifying differentially expressed genes (DEGs) in MTX‐resistant PCa xenografts. Human PCa cell lines DU145 and PC3 were cultured in vitro and xenografted into severe combined immunodeficiency (SCID) mice, treated with MTX intragastrically, three times a week until all mice relapsed. Gene expression profiles of the xenografts from castrated mice were performed with Affymetrix human whole genomic oligonucleotide microarray. The Cytoscape software was used to investigate the relationship between proteins and the signalling transduction network. A total of 355 overlapping genes were differentially expressed in MTX‐resistant DU145R and PC3R xenografts. Of these, 16 genes were selected to be validated by quantitative real‐time PCR (qRT‐PCR) in these xenografts, and further tested in a set of formalin‐fixed, paraffin‐embedded and optimal cutting temperature (OCT) clinical tumour samples. Functional and pathway enrichment analyses revealed that these DEGs were closely related to cellular activity, androgen synthesis, DNA damage and repair, also involved in the ERK/MAPK, PI3K/serine‐threonine protein kinase, also known as protein kinase B, PKB (AKT) and apoptosis signalling pathways. This exploratory analysis provides information about potential candidate genes and may bring new insights into the molecular cascade involvement in MTX‐resistant PCa.

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“…19 chemotherapeutic drug for many types of cancer, we chose HeLa cells as it has specifically been shown to induce inter-strand cross-links in DNA of tumorigenic HeLa cells [71]. We quantified the cytotoxicity using the WST-1 reagent in 96-well assays.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%