Doxorubicin‐induced lipid peroxidation and glutathione peroxidase activity in tumor cell lines selected for resistance to doxorubicin

Benchekroun, Mohamed Nabil; Pourquier, Philippe; Schott, Brigitte; Robert, Jacques

doi:10.1111/j.1432-1033.1993.tb19880.x

Cited by 50 publications

(27 citation statements)

References 26 publications

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“…24,25) Thus, we examined the effects of citrulline using LPO as an indicator of DOX cardiotoxicity, and observed significant inhibition of DOX-induced LPO accumulation in the heart. It is suggested that these effects were related to antioxidant activities, involving scavenging of hydroxyl radicals by citrulline.…”

Section: Discussionmentioning

confidence: 99%

Improvements of Doxorubicin-Induced Antitumor Activity and Adverse Reaction by Combined Citrulline

Miyashita

Sadzuka

2014

Biological & Pharmaceutical Bulletin

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Citrulline is an amino acid with antioxidant activity. In this study, effects of citrulline on the adverse effects of doxorubicin (DOX) and DOX-induced antitumor activity were examined. Citrulline significantly inhibited DOX-induced increases in lipid peroxide (LPO) in the heart as adverse reaction. Combined treatment with DOX and citrulline increased DOX levels in tumor cells and enhanced cytotoxicity in vitro by significantly increasing DOX uptake compared with DOX treatment alone. In simultaneous in vivo treatments, combination treatment with DOX and citrulline decreased tumor weight and increased DOX concentrations in tumors. Promotion of DOX uptake by citrulline enhanced the antitumor activity of DOX through the action of energy-independent and Na -independent transporters. This effect of citrulline on DOX influx is identical to that of S-(4-nitrobenzyl)-6-thioinosine, promoting DOX influx through the equilibrative nucleoside transporter 1. Therefore, it is anticipated that citrulline as a food component may enhance DOX efficacy.Key words citrulline; doxorubicin; adverse reaction; antitumor activity; doxorubicin permeability Currently, cancer therapies include surgery, radiation therapy, and chemotherapy, which is appropriate for hematological tumors and general metastases. Among cancer chemotherapies, alkylating agents, antimetabolites, plant alkaloids, antitumor antibiotics platinum compounds, and molecular targeting agents are used. Furthermore, because mechanisms of antitumor agents vary, combined therapies offer clinical potential to enhance antitumor activity and reduce adverse reactions. [1][2][3][4][5] In contrast, while some biochemical modulators without antitumor activity enhance the pharmacological properties of antitumor agents, these can improve the therapeutic indexes or ameliorate adverse reactions by antitumor agents. However, these therapies often enhance antitumor agent induced adverse reactions with the increase in antitumor activity. Hence, developments and discoveries of novel modulators that enhance antitumor activities and reduce adverse reactions to antitumor agents are required.The anthracycline doxorubicin (DOX) is widely used to treat a variety of malignancies, despite the severity of associated adverse reactions, such as cardiotoxicity. Although many studies report enhancement of DOX antitumor activity in tumor cells by direct inhibition of DOX efflux, no agents or combinations have been found to increase the therapeutic index of DOX by expression of these efflux pumps in normal tissues. Previously, we reported improved DOX-induced antitumor activity using the food components caffeine, theanine, and cucurbitacins. [6][7][8][9][10][11][12][13][14][15] It appeared that these effects were mediated by increased DOX concentration in the tumors, which suppress DOX efflux from tumor cells. In contrast, linalool promoted DOX influx into tumor cells and enhanced its activity by acting on the Na + -dependent nucleoside transporter (CNT) 3.16) Furthermore, decreases in DOX levels following...

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Section: Discussionmentioning

confidence: 99%

Improvements of Doxorubicin-Induced Antitumor Activity and Adverse Reaction by Combined Citrulline

Miyashita

Sadzuka

2014

Biological & Pharmaceutical Bulletin

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“…It was shown that the liver has higher cytochrome-P450 reductase level than does cardiac tissue (Myers et al 1982). The semiquinone subsequently reacts with oxygen, iron, and hydrogen peroxide to produce ROS causing apoptosis and cell damage (Benchekroun et al 1993;Chen et al 2013). Therefore, oxidative stress induced in rat liver by ADR was found to be higher than in the controls in our current study.…”

Section: Discussionmentioning

confidence: 44%

“…*p \ 0.05 versus ADR. All data were expressed as mean ± SEM mitochondria electron transport system (Chen et al 2013) from mainly cytochrome-P450 reductase enzyme (Benchekroun et al 1993) which is important for the metabolism of both endogenous (e.g. lipids, steroids) and exogenous (e.g.…”

Section: Discussionmentioning

confidence: 99%

Recovery of adriamycin induced mitochondrial dysfunction in liver by selenium

Taşkın

Dursun

2014

Cytotechnology

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Adriamycin (ADR) is a chemotherapeutic drug. Its toxicities may associate with mitochondriopathy. Selenium (Se) is a trace element for essential intracellular antioxidant enzymes. However, there is lack of data related to the effect of selenium on the liver tissue of ADR-induced mitochondrial dysfunction. The study was to investigate whether Se could restore mitochondrial dysfunction of liver-exposed ADR. Rats were divided into four groups as a control, ADR, Se, co-treated ADR with Se groups. The biochemical measurements of the liver were made in mitochondrial and cytosol. ATP level and mitochondria membrane potential (MMP) were measured. Total oxidant (TOS), total antioxidant (TAS) status were determined and oxidative stress index (OSI) was calculated by using TOS and TAS. ADR increased TOS in mitochondria and also oxidative stress in mitochondria. ADR sligtly decreased MMP, and ATP level. Partial recovery of MMP by Se was able to elevate the ATP production in cotreatment of ADR with Se. TOS in mitochondria and cytosol was diminished, as well as OSI. We concluded that selenium could potentially be used against oxidative stress induced by ADR in liver, resulting from the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.

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“…Incubation with radical scavengers caused cell viability to return to the baseline level of doxorubicin in the absence of polyunsaturated fatty acids (Germain et al, 1998). Moreover, in a doxorubicin-resistant mammary tumour cell line, lipid peroxidation levels were found to be lower than in the wild-type cell line (Benchekroun et al, 1993). These data point towards the notion that lipid peroxidation may be a general mechanism by which the permeability of tumour cell membranes may be increased for doxorubicin and its anthracycline derivatives.…”

Section: mentioning

confidence: 88%

Increased doxorubicin uptake and toxicity in multicellular tumour spheroids treated with DC electrical fields

et al. 1999

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Electrochemotherapy (ECT) is a promising new approach to fighting cancer and has successfully been applied to regressing tumours in several animal models and clinical trials with squamous cell carcinomas, basal cell carcinomas, metastatic melanomas and liver tumours (Sersa et al, 1995;Glass et al, 1996;Heller et al, 1996;Mir et al, 1997;Ramirez et al, 1998, Belehradek et al, 1993. During ECT treatment, antineoplastic drugs with low cell membrane permeability, e.g. bleomycin (Poddevin et al, 1991), are delivered into cells by short and intense electric field pulses. These field pulses with a field strength of approximately 130 000 Vm -1 are applied for microseconds and have been discussed to transiently increase the permeability of cell membranes by electroporation Nishi et al, 1997). Owing to the high field strength of the applied electrical fields, pulses have to be administered locally at the solid tumour site of avoid serious side-effects of the electrical field on the patient. This implicates that the enhanced delivery of the anticancer agent is restricted to the area that has been electrically treated. Unlocalized tumours, however, remain untreated, making desirable an ECT approach that uses fairly lower field strengths which can be more generally applied to tissues or whole organs.In the present study, we used multicellular prostate tumour spheroids of the DU-145 cell line to investigate whether treatment with low electrical field strengths increases the uptake and toxicity of the cell membrane-permeant anthracycline doxorubicin. Tumour spheroids were treated for 90 s with a single electrical field pulse of a field strength that has previously been shown to stimulate tumour cell proliferation Wartenberg et al, 1997). An experimental approach for ECT based on stimulation of cell proliferation should be promising since chemotherapeutics are known to be far more effective in rapid cycling as compared to slow-cycling tumour cells.  Culture technique of multicellular tumour spheroidsThe human prostate cancer cell line DU-145 was kindly provided by Dr J Carlsson, Uppsala, Sweden. Cells were cultured in Ham's F10 medium (Gibco, Live Technologies, Helgerman Court, MD, USA) as described previously (Sauer et al, 1997) Spheroids were grown from single cells (passages 2-15) seeded in 250 ml siliconated spinner flasks (Tecnomara, Fernwald, Germany) at 1 × 10 5 cells ml -1. The spinner flask medium (175 ml) was stirred (20 rpm) using a stirrer system (Tecnomara) and partly changed every day. For the experiments, tumour spheroids of a size class of 150 ± 30 µm were used. Enzymatic dissociation of multicellular tumour spheroidsDissociation of multicellular spheroids was performed as described previously . In brief, spheroids were washed in phosphate-buffered saline (PBS) and placed in a Summary Electrochemotherapy (ECT) is a new approach to the treatment of tumours. In the present study, multicellular prostate tumour spheroids were treated with non-lethal direct current (DC) electrical fields, and upt...

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Doxorubicin‐induced lipid peroxidation and glutathione peroxidase activity in tumor cell lines selected for resistance to doxorubicin

Cited by 50 publications

References 26 publications

Improvements of Doxorubicin-Induced Antitumor Activity and Adverse Reaction by Combined Citrulline

Improvements of Doxorubicin-Induced Antitumor Activity and Adverse Reaction by Combined Citrulline

Recovery of adriamycin induced mitochondrial dysfunction in liver by selenium

Increased doxorubicin uptake and toxicity in multicellular tumour spheroids treated with DC electrical fields

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