دورية أكاديمية
Preclinical genotoxicology of nor-β-lapachone in human cultured lymphocytes and Chinese hamster lung fibroblasts.
| العنوان: | Preclinical genotoxicology of nor-β-lapachone in human cultured lymphocytes and Chinese hamster lung fibroblasts. |
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| المؤلفون: | Cavalcanti BC; National Laboratory of Experimental Oncology, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil. nunim_br@yahoo.com.br, Barros FW, Cabral IO, Ferreira JR, Magalhães HI, Júnior HV, da Silva Júnior EN, de Abreu FC, Costa CO, Goulart MO, Moraes MO, Pessoa C |
| المصدر: | Chemical research in toxicology [Chem Res Toxicol] 2011 Sep 19; Vol. 24 (9), pp. 1560-74. Date of Electronic Publication: 2011 Aug 23. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 8807448 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5010 (Electronic) Linking ISSN: 0893228X NLM ISO Abbreviation: Chem Res Toxicol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: Washington, DC : American Chemical Society, c1988- |
| مواضيع طبية MeSH: | Antineoplastic Agents/*toxicity , Fibroblasts/*drug effects , Lung/*cytology , Lymphocytes/*drug effects , Mutagens/*toxicity , Naphthoquinones/*toxicity, Animals ; Cell Survival/drug effects ; Cells, Cultured ; Cricetinae ; DNA/metabolism ; DNA Damage/drug effects ; Fibroblasts/cytology ; HL-60 Cells ; Humans ; Lymphocytes/cytology ; Neoplasms/drug therapy ; Oxidative Stress/drug effects ; Sulfhydryl Compounds/metabolism |
| مستخلص: | Nor-β-lapachone has shown several biological properties. Regarding cytotoxic activity against cancer cell lines, it has been recognized as an important prototype. However, quinonoid drugs present a major challenge because of their toxicity. In this study, we evaluated the cytotoxicity and genetic toxicity of nor-β-lapachone in human lymphocytes and HL-60 leukemia cells and murine V79 fibroblasts, to shed some light on its selectivity toward cancer cells. As measured by MTT test, exposure of V79 cells to nor-β-lapachone resulted in a weak cytotoxicity (IC(50) = 13.41 μM), and at a concentration up to 21.9 μM, no cytotoxic effect was observed in lymphocytes, while in HL-60 cells, nor-β-lapachone elicited significantly greater cytotoxicity (IC(50) = 1.89 μM). Cultures coexposed to GSH-OEt showed an increased viability, which may indicate a neutralization of ROS generated by quinonoid treatment. In fact, only the highest concentrations of nor-β-lapachone (10 or 20 μM) caused an increase in oxidative stress in nontumor levels cells as measured by TBARS and nitrite/nitrate detection. This was accompanied by an alteration in intracellular thiol content. However, NAC pre-exposure restored the redox equilibrium of the cells and the concentration of thiol levels to control values. Nor-β-lapachone at 2.5 and 5 μM failed to induce DNA damage in nontumor cells, but at the highest concentrations tested, it induced single and double DNA strand breaks and increased the frequency of chromosomal aberrations. Interestingly, these damages were prevented by NAC pretreatment or exacerbated by prior exposure to the GSH-depleting agent 1-bromoheptane. In electrochemical experiments, nor-β-lapachone at the same concentrations as those used in genotoxic tests did not damage DNA directly, but at the highest concentration tested (200 μM), it caused a very weak DNA interaction. Corroborating electrochemical data, oxidative modifications of DNA bases were observed, as checked by DNA repair enzymes EndoIII and FPG, which reinforced the indirect actions caused by nor-β-lapachone through ROS generation and not via DNA intercalation. The DNA repair capacities were higher for nontumor cells than for leukemia cells, which may be related to the selective cytoxicity of nor-β-lapachone toward cancer cells. Our data suggest that ROS play an important role in nor-β-lapachone toxicity and that its DNA-damaging effect occurs only at concentrations several times higher than that needed for its antiproliferative effect on cancer cells. |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Mutagens) 0 (Naphthoquinones) 0 (Sulfhydryl Compounds) 6N4FA2QQ6A (beta-lapachone) 9007-49-2 (DNA) |
| تواريخ الأحداث: | Date Created: 20110812 Date Completed: 20120118 Latest Revision: 20220718 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1021/tx200180y |
| PMID: | 21830773 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-5010 |
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| DOI: | 10.1021/tx200180y |