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Expression profiling identifies epoxy anthraquinone derivative as a DNA topoisomerase inhibitor.

ABSTRACT: To discover novel drugs for neuroblastoma treatment, we have previously screened a panel of drugs and identified 30 active agents against neuroblastoma cells. Here we performed microarray gene expression analysis to monitor the impact of these agents on a neuroblastoma cell line and used the connectivity map (cMAP) to explore putative mechanism of action of unknown drugs. We first compared the expression profiles of 10 compounds shared in both our dataset and cMAP database and observed the high connectivity scores for 7 of 10 matched drugs regardless of the differences of cell lines utilized. The screen of cMAP for uncharacterized drugs indicated the signature of Epoxy anthraquinone derivative (EAD) matched the profiles of multiple known DNA targeted agents (topoisomerase I/II inhibitors, DNA intercalators, and DNA alkylation agents) as predicted by its structure. Similar result was obtained by querying against our internal NB-cMAP (http://pob.abcc.ncifcrf.gov/cgi-bin/cMAP), a database containing the profiles of 30 active drugs. These results suggest that Epoxy anthraquinone derivative may inhibit neuroblastoma cells by targeting DNA replication inhibition. Experimental data also demonstrate that Epoxy anthraquinone derivative indeed induces DNA double-strand breaks through DNA alkylation and inhibition of topoisomerase activity. Our study indicates that Epoxy anthraquinone derivative may be a novel DNA topoisomerase inhibitor that can be potentially used for treatment of neuroblastoma or other cancer patients.

SUBMITTER: Gheeya J

PROVIDER: S-EPMC4698332 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Expression profiling identifies epoxy anthraquinone derivative as a DNA topoisomerase inhibitor.

Gheeya Jinesh J Johansson Peter P Chen Qing-Rong QR Dexheimer Thomas T Metaferia Belhu B Song Young K YK Wei Jun S JS He Jianbin J Pommier Yves Y Khan Javed J

Cancer letters 20100204 1

To discover novel drugs for neuroblastoma treatment, we have previously screened a panel of drugs and identified 30 active agents against neuroblastoma cells. Here we performed microarray gene expression analysis to monitor the impact of these agents on a neuroblastoma cell line and used the connectivity map (cMAP) to explore putative mechanism of action of unknown drugs. We first compared the expression profiles of 10 compounds shared in both our dataset and cMAP database and observed the high ...[more]

PMID: 20133050

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Project description:BackgroundTopoisomerase II is critical for DNA replication, transcription and chromosome segregation and is a well validated target of anti-neoplastic drugs including the anthracyclines and epipodophyllotoxins. However, these drugs are limited by common tumor resistance mechanisms and side-effect profiles. Novel topoisomerase II-targeting agents may benefit patients who prove resistant to currently available topoisomerase II-targeting drugs or encounter unacceptable toxicities. Voreloxin is an anticancer quinolone derivative, a chemical scaffold not used previously for cancer treatment. Voreloxin is completing Phase 2 clinical trials in acute myeloid leukemia and platinum-resistant ovarian cancer. This study defined voreloxin's anticancer mechanism of action as a critical component of rational clinical development informed by translational research.Methods/principal findingsBiochemical and cell-based studies established that voreloxin intercalates DNA and poisons topoisomerase II, causing DNA double-strand breaks, G2 arrest, and apoptosis. Voreloxin is differentiated both structurally and mechanistically from other topoisomerase II poisons currently in use as chemotherapeutics. In cell-based studies, voreloxin poisoned topoisomerase II and caused dose-dependent, site-selective DNA fragmentation analogous to that of quinolone antibacterials in prokaryotes; in contrast etoposide, the nonintercalating epipodophyllotoxin topoisomerase II poison, caused extensive DNA fragmentation. Etoposide's activity was highly dependent on topoisomerase II while voreloxin and the intercalating anthracycline topoisomerase II poison, doxorubicin, had comparable dependence on this enzyme for inducing G2 arrest. Mechanistic interrogation with voreloxin analogs revealed that intercalation is required for voreloxin's activity; a nonintercalating analog did not inhibit proliferation or induce G2 arrest, while an analog with enhanced intercalation was 9.5-fold more potent.Conclusions/significanceAs a first-in-class anticancer quinolone derivative, voreloxin is a toposiomerase II-targeting agent with a unique mechanistic signature. A detailed understanding of voreloxin's molecular mechanism, in combination with its evolving clinical profile, may advance our understanding of structure-activity relationships to develop safer and more effective topoisomerase II-targeted therapies for the treatment of cancer.

Project description:Kinetoplast DNA (kDNA) bearing unusual mitochondrion of trypanosomatid parasites offers a new paradigm in chemotherapy modality. Topoisomerase II of Leishmania donovani (LdTopII), a key enzyme associated with kDNA replication, is emerging as a potential drug target. However, mode of action of LdTopII targeted compounds in the parasites at sub-cellular level remains largely unknown. Previously, we reported that an isobenzofuranone derivative, namely 3,5-bis(4-chlorophenyl)-7-hydroxyisobenzofuran-1(3H)-one (JVPH3), targets LdTopII and induces apoptosis-like cell death in L. donovani. Here, we elucidate the phenotypic changes and the events occurring at sub-cellular level caused by JVPH3 in L. donovani. In addition, we have evaluated the cytotoxicity and ultrastructural alterations caused by JVPH3 in two brazilian trypanosomatid pathogens viz. L. amazonensis and Trypanosoma cruzi. Despite killing these parasites, JVPH3 caused significantly different phenotypes in L. donovani and L. amazonensis. More than 90% population of parasites showed altered morphology. Mitochondrion was a major target organelle subsequently causing kinetoplast network disorganization in Leishmania. Altered mitochondrial architecture was evident in 75-80% Leishmania population being investigated. Quantification of mitochondrial function using JC-1 fluorophore to measure a possible mitochondrial membrane depolarization further confirmed the mitochondrion as an essential target of the JVPH3 corroborating with the phenotype observed by electron microscopy. However, the impact of JVPH3 was lesser on T. cruzi than Leishmania. The molecule caused mitochondrial alteration in 40% population of the epimastigotes being investigated. To our knowledge, this is the first report to evaluate the proliferation pattern and ultrastructural alterations caused in Brazilian kinetoplastid pathogens by a synthetic LdTopII inhibitor previously established to have promising in vivo activity against Indian strain of L. donovani.

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Expression profiling identifies epoxy anthraquinone derivative as a DNA topoisomerase inhibitor.

Publications

Expression profiling identifies epoxy anthraquinone derivative as a DNA topoisomerase inhibitor.

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