DNA damage induced by the anthracycline cosmomycin D in DNA repair-deficient cells

Carvalho, Helotônio; Garrido, Leandro M.; Furlan, Renata Ligia de Araujo; Padilla, Gabriel; Agnoletto, Mateus H.; Guecheva, Temenouga Nikolova; Henriques, João Antônio Pêgas; Saffi, Jenifer; Menck, Carlos Frederico Martins

doi:10.1007/s00280-010-1244-x

Cited by 19 publications

(19 citation statements)

References 26 publications

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“…Furthermore, doxorubicin caused greater DNA damage in normal than in tumor cells when compared to coronaridine. Carvalho et al (2010) compared the effect of the anthracycline cosmomycin D and doxorubicin in DNA repair-deficient cell lines (XP-A and XP-C). Treatment of XP-A and XP-C cells with cosmomycin D induced apoptosis in a time-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity and genotoxicity of coronaridine from Tabernaemontana catharinensis A.DC in a human laryngeal epithelial carcinoma cell line (Hep-2)

et al. 2013

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Cancer has become a major public health problem worldwide and the number of deaths due to this disease is increasing almost exponentially. In the constant search for new treatments, natural products of plant origin have provided a variety of new compounds to be explored as antitumor agents. Tabernaemontana catharinensis is a medicinal plant that produces alkaloids with expressive antitumor activity, such as heyneanine, coronaridine and voacangine. The aim of present study was firstly to screen the cytotoxic activity of the indole alkaloids heyneanine, coronaridine and voacangine against HeLa (human cervix tumor), 3T3 (normal mouse embryo fibroblasts), Hep-2 (human laryngeal epithelial carcinoma) and B-16 (murine skin) cell lines by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide); and secondly to analyze the apoptotic activity, cell membrane damage and genotoxicity of the compound that showed the best cytotoxic activity against the tumor cell lines tested. Coronaridine was the one that exhibited greater cytotoxic activity in the laryngeal carcinoma cell line Hep-2 (IC50 = 54.47 μg/mL) than the other alkaloids tested (voacangine IC50 = 159.33 g/mL, and heyneanine IC50 = 689.45 μg/mL). Coronaridine induced apoptosis in cell lines 3T3 and Hep-2, even at high concentrations. The evaluation of genotoxicity by comet assay showed further that coronaridine caused minimal DNA damage in the Hep-2 tumor cell line, and the LDH test showed that it did not affect the plasma membrane. These results suggest that further investigation of coronaridine as an antitumor agent has merit.

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Section: Discussionmentioning

confidence: 99%

Cytotoxicity and genotoxicity of coronaridine from Tabernaemontana catharinensis A.DC in a human laryngeal epithelial carcinoma cell line (Hep-2)

et al. 2013

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“…Development of resistance to chemotherapeutic drugs poses a serious limitation to the effectiveness of treatment [10,11]. For example, it has been shown that acquired resistance to Pt accounted for treatment failure and deaths in up to 90% of patients with ovarian cancer [12].…”

Section: Introductionmentioning

confidence: 99%

Increased γ-H2AX and Rad51 DNA Repair Biomarker Expression in Human Cell Lines Resistant to the Chemotherapeutic Agents Nitrogen Mustard and Cisplatin

et al. 2014

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Chemotherapeutic anticancer drugs mediate cytotoxicity by a number of mechanisms. However, alkylating agents which induce DNA interstrand crosslinks (ICL) are amongst the most effective anticancer agents and often form the mainstay of many anticancer therapies. The effectiveness of these drugs can be limited by the development of drug resistance in cancer cells and many studies have demonstrated that alterations in DNA repair kinetics are responsible for drug resistance. In this study we developed two cell lines resistant to the alkylating agents nitrogen mustard (HN2) and cisplatin (Pt). To determine if drug resistance was associated with enhanced ICL DNA repair we used immunocytochemistry and imaging flow cytometry to quantitate the number of γ-H2AX and Rad51 foci in the nuclei of cells after drug exposure. γ-H2AX was used to evaluate DNA strand breaks caused by repair incision nucleases and Rad51 was used to measure the activity of homologous recombination in the repair of ICL. In the drug-resistant derivative cell lines there was overall a significant increase in the number and persistence of both γ-H2AX and Rad51 foci in the nuclei of cells over a 72-hour period, when compared to the non-resistant parental cell lines (ANOVA p < 0.0001). In a Pt-resistant ovarian cancer cell line (A2780cis^R) a similar enhancement of DNA repair was observed when compared to the non-drug-resistant wild-type ovarian cancer cells (A2780) following exposure to HN2. Our data suggest that using DNA repair biomarkers to evaluate mechanisms of resistance in cancer cell lines and human tumours may be of experimental and clinical benefit. We concede, however, that examination of a larger population of cell lines and tumours is required to fully evaluate the validity of this approach.

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“…Furthermore, the high intracellular GSH concentration can result in the formation of aggregates of the DOX loaded micelle cores, which remain in the cells favourably and reduce the efflux of drug out of cells further . Hence more DOX can get into the nuclei of cancer cells to stop DNA replication, inhibit macromolecular synthesis, and ultimately kill the cancer cells …”

Section: Resultsmentioning

confidence: 99%

pH‐ and Redox‐Responsive Poly(ethylene glycol) and Cholesterol‐Conjugated Poly(amido amine)s Based Micelles for Controlled Drug Delivery

Cheng

Kumar

Zhang

et al. 2013

Macromolecular Bioscience

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An optimized condition is identified to prepare linear poly(amido amine)s via Michael Addition polymerization of trifunctional amine, 4-(aminomethyl)piperidine (AMPD), with an equimolar diacrylamide, N,N-cystaminebis(acrylamide) (BAC). Poly(ethylene glycol) (PEG) and cholesterol (CE) are conjugated to linear poly(BAC-AMPD) through the reactions with the secondary amino groups in the backbone, respectively, to form poly(BAC-AMPD)-g-PEG-g-CE. The chemical structures of poly(BAC-AMPD) and poly(BAC-AMPD)-g-PEG-g-CE are characterized using NMR and gel permeation chromatography (GPC). Transmission electron microscopy (TEM), dynamic light scattering (DLS) and (1)H NMR results show that micelles with PEG shells and hydrophobic cores composed of poly(BAC-AMPD) and CE are formed via self-assembly of poly(BAC-AMPD)-g-PEG-g-CE in aqueous solution, and the micelles of poly(BAC-AMPD)-g-PEG-g-CE can be degraded by the presence of L-dithiothreitol and show a limited cytotoxicity in vitro. The anti-cancer drug, doxorubicin (DOX), can be loaded into the micelles. The DOX loaded micelles of poly(BAC-AMPD)-g-PEG-g-CE show pH- and redox-responsive drug release and redox-induced formation of aggregates, and it is shown that the DOX loaded micelles can deliver DOX into cells and show a higher efficacy in killing cancer cells than free drug.

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DNA damage induced by the anthracycline cosmomycin D in DNA repair-deficient cells

Cited by 19 publications

References 26 publications

Cytotoxicity and genotoxicity of coronaridine from Tabernaemontana catharinensis A.DC in a human laryngeal epithelial carcinoma cell line (Hep-2)

Cytotoxicity and genotoxicity of coronaridine from Tabernaemontana catharinensis A.DC in a human laryngeal epithelial carcinoma cell line (Hep-2)

Increased γ-H2AX and Rad51 DNA Repair Biomarker Expression in Human Cell Lines Resistant to the Chemotherapeutic Agents Nitrogen Mustard and Cisplatin

pH‐ and Redox‐Responsive Poly(ethylene glycol) and Cholesterol‐Conjugated Poly(amido amine)s Based Micelles for Controlled Drug Delivery

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DNA damage induced by the anthracycline cosmomycin D in DNA repair-deficient cells

Cited by 19 publications

References 26 publications

Cytotoxicity and genotoxicity of coronaridine from Tabernaemontana catharinensis A.DC in a human laryngeal epithelial carcinoma cell line (Hep-2)

Cytotoxicity and genotoxicity of coronaridine from Tabernaemontana catharinensis A.DC in a human laryngeal epithelial carcinoma cell line (Hep-2)

Increased &#947;-H2AX and Rad51 DNA Repair Biomarker Expression in Human Cell Lines Resistant to the Chemotherapeutic Agents Nitrogen Mustard and Cisplatin

pH‐ and Redox‐Responsive Poly(ethylene glycol) and Cholesterol‐Conjugated Poly(amido amine)s Based Micelles for Controlled Drug Delivery

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Increased γ-H2AX and Rad51 DNA Repair Biomarker Expression in Human Cell Lines Resistant to the Chemotherapeutic Agents Nitrogen Mustard and Cisplatin