Release of iron from ferritin by semiquinone, anthracycline, bipyridyl, and nitroaromatic radicals

The cytotoxicity of many xenobiotics is related to their ability to undergo redox reactions and iron dependent free radical reactions. We have measured the ability of a number of redox active compounds to release iron from the cellular iron storage protein, ferritin. Compounds were reduced to their corresponding radicals with xanthine oxidase/hypoxanthine under N₂ and the release of Fe²⁺ was monitored by complexation with ferrozine. Ferritin iron was released by a number of bipyridyl radicals including those derived from diquat and paraquat, the anthracycline radicals of adriamycin, daunorubicin and epirubicin, the semiquinones of anthraquinone-2-sulphonate, 1,5 and 2,6-dihydroxyanthraquinone, 1-hydroxyanthraquinone, purpurin, and plumbagin, and the nitroaromatic radicals of nitrofurantoin and metronidazole. In each case, iron release was more efficient than with an equivalent flux of superoxide. Introduction of air decreased the rate of iron release, presumably because the organic radicals reacted with O₂ to form superoxide. In air, iron release was inhibited by superoxide dismutase. Semiquinones of menadione, benzoquinone, duroquinone, anthraquinone 1,5 and 2,6-disulphonate, 1,4 naphthoquinone-2-sulphonate and naphthoquinone, when formed under N₂, were unable to release ferrin iron. In air, these systems gave low rates of superoxide dismutase-inhibitible iron release. Of the compounds investigated, those with a single electron reduction potential less than that of ferritin were able to release ferritin iron.     

Effects of peroxidase substrates on the Amplex red/peroxidase assay: antioxidant properties of anthracyclines

Oxidation of Amplex red (AR) by H(2)O(2) in the presence of horseradish peroxidase (HRP) gives rise to an intensely colored product, resorufin. This reaction has been frequently employed for measurements of low concentrations of H(2)O(2) in biological samples. In the current study, we show that alternative peroxidase substrates, such as p-hydroquinone, acetaminophen, anticancer mitoxantrone, and ametantrone, inhibit AR oxidation by consuming H(2)O(2) in a competitive process. In contrast, the anthracycline agents doxorubicin, daunorubicin, and 5-iminodaunorubicin are markedly less efficient as competitors in these reactions, as is salicylic acid. When [H(2)O(2)]>[AR], the generated resorufin was oxidized by HRP and H(2)O(2). In the presence of anthracyclines, this process was inhibited and occurred with a lag time, the duration of which depended on the concentration of anthracycline. We propose that the mechanism of this inhibition is due to the antioxidant activity of anthracyclines involving the reduction of the resorufin-derived phenoxyl radical by the drugs' hydroquinone moiety back to resorufin. In addition to HRP, lactoperoxidase, myeloperoxidase, and HL-60 cells, naturally rich in myeloperoxidase, also supported these reactions. Results of this study suggest that extra caution is needed when using AR to measure cellular H(2)O(2) in the presence of alternative peroxidase substrates. They also demonstrate that the anticancer anthracyclines may function as antioxidants.     

Alterations in myocardial energy metabolism induced by the anti-cancer drug doxorubicin

Doxorubicin and other anthracyclines are among the most potent chemotherapeutic drugs for the treatment of acute leukaemia, lymphomas and different types of solid tumours such as breast, liver and lung cancers. Their clinical use is, however, limited by the risk of severe cardiotoxicity, which can lead to irreversible congestive heart failure. There is increasing evidence that essential components of myocardial energy metabolism are among the highly sensitive and early targets of doxorubicin-induced damage. Here we review doxorubicin-induced detrimental changes in cardiac energetics, with an emphasis on the emerging importance of defects in energy-transferring and -signalling systems, like creatine kinase and AMP-activated protein kinase.     

Synthesis and antibacterial activity of aminosugar-functionalized intercalating agents

A series of previously reported amino sugar-functionalized intercalating agents, 3-14, were evaluated in two antibacterial assays (paper disk diffusion and 96-well microdilution) against Bacillus atrophaeus, ATCC 9372 and Escherichia coli, ATCC 47076. Although none of the compounds were active against this E. coli strain, several showed activity against B. atrophaeus. In anticipation of the need for larger amounts of these compounds for future structure-activity relationship studies, improved routes to 11-14 were developed.     

Combined effect of low-power laser irradiation and anthraquinone anticancer drug aclarubicin on survival of immortalized cells: Comparison with mitoxantrone

The photodynamic response of the anthraquinone anticancer drug aclarubicin (ACL) was investigated in vitro and compared with that of mitoxantrone (MTX). Cultured immortalized rodent B14 and NIH 3T3 cells were used in the experiments as a model for cells with neoplastic phenotype. Long-term cytotoxicity and inhibition of cell proliferation assayed by the clonal growth and MTT-tetrazolium methods were estimated to compare the efficacy of aclarubicin and mitoxantrone in photosensitizing cells and their death after non-thermal exposure to monochromatic laser light. Green He-Ne (543.5 nm) or red semiconductor (670 nm) low-power laser (LPL) irradiations were applied. Different dose-responses of both cell lines to aclarubicin and mitoxantrone were found so that the cytotoxicity of MTX was considerably greater than the cytotoxicity of ACL. Phototherapy response (P < 0.0001) was observed only for B14 cells after sensitisation with aclarubicin. Under the same conditions no significant effect of red light irradiation (semiconductor 670 nm laser) on survival of both cell lines treated with mitoxantrone was found.     

Separation methods for anthraquinone related anti-cancer drugs

The quinoid anthracycline-related anti-cancer agents represent an important group of anti-tumour drugs with a wide spectrum of activity. We review here some of the separation techniques used for the analysis of anthracyclines and related compounds. In this review we have covered a range of compounds from the early anthracycline antibiotics such as doxorubicin to the more recent anthracenediones and anthrapyrazoles such as mitoxantrone and losoxantrone, respectively. We also include novel compounds such as AQ4N and C1311, both awaiting clinical trial. Separations of the anthraquinone related anti-cancer agents are predominantly by HPLC. These separation techniques have been used for a variety of applications including drug stability, protein binding and therapeutic drug monitoring as well as detailed pharmacokinetic and metabolic studies. Pharmacokinetics, and therefore drug analysis, plays a central role in both the development of new agents and also leads to a better understanding of clinically established agents in this class. Sample preparation and extraction methods including solid-phase and liquid–liquid extraction have also been highlighted. Many anthraquinone related compounds are highly coloured and fluoresce. They are suitable for a range of detection methods including UV–Vis, electrochemical and fluorescence. The methods described are used for sometimes complex separations that are needed for the evaluation of such compounds in biological samples.     

血清cTnI、TFF1检测在乳腺癌化疗相关心脏毒性预测中的价值

摘要 目的：探讨血清心肌肌钙蛋白I（Cardiac,Troponin I,cTnI）、三叶因子1（trefoil factor 1,TFF1）检测在乳腺癌化疗相关心脏毒性预测中的价值。方法：2018年2月到2021年2月选择在本院接受蒽环类药物化疗的乳腺癌患者122例作为研究对象,所有患者都给予蒽环类药物化疗,在化疗前检测血清cTnI、TFF1含量,在化疗4个周期后观察心脏毒性反应发生情况并进行预测价值分析。结果：122例乳腺癌患者根据表阿霉素化疗累积剂量分为低剂量组（450-500 mg/m2）70例、中剂量组（501-550 mg/m2）30例、高剂量组（>550 mg/m2）22例;三组化疗前的血清cTnI、TFF1含量对比差异无统计学意义（P>0.05）。低剂量组、中剂量组、高剂量组化疗后的心电图异常率分别为1.4 %、13.3 %和22.7 %,对比差异有统计学意义（P<0.05）。在122例患者中,Pearson分析显示心电图异常与cTnI、TFF1、化疗剂量都存在相关性（P<0.05）。受试者工作特征（receiver operating characteristic,ROC）曲线显示cTnI、TFF1预测心电图异常的曲线下面积分别为0.782、0.706。结论：乳腺癌患者使用蒽环类药物化疗存在一定的心脏毒性反应,且存在剂量依赖性,血清cTnI、TFF1检测能有效预测化疗相关心脏毒性的发生,具有很好的临床应用价值。