Antitumour activity of some plants from Meghalaya and Mizoram against murine ascites Dalton's lymphoma

Total five plants, three from Mizoram (Dillenia pentagyna, Ageratum conyzoides, Blumea lanceolaria) and two from Meghalaya (Potentilla fulgens, Taxus baccata) were studied for their antitumour activity against murine ascites Dalton's lymphoma (DL) in vivo. Only three plants showed the different magnitude of antitumour activity. Out of these three plants, the antitumour activity was maximally observed with the methanol extract of the stem bark of D. pentagyna as compared to the aqueous extract of the roots of A. conyzoides and aqueous extract of the root of P. fulgens. An increase in glutathione levels in Dalton's lymphoma cells was observed during tumour growth. Changes in glutathione and protein levels were also investigated in the liver and Dalton's lymphoma cells of tumour-bearing mice following the treatment with the extract of D. pentagyna which showed the highest antitumour activity as compared to the other two plant extracts. Glutathione in the liver and DL cells of treated tumour-bearing mice was found to be decreased. The protein concentration in liver and DL cells decreased mainly at 96 hr of treatment. It may be concluded that the natural product of D. pentagyna promises to be more active against Dalton's lymphoma than others and the decrease in glutathione level may be one of the important steps in resulting this antitumour effect.     

Influence of resveratrol on oxidative damage in genomic DNA and apoptosis induced by cisplatin

Cisplatin is a potent chemotherapeutic agent that has gained widespread use against various malignant tumours in a variety of human malignancies. Like other chemotherapeutic agents, cisplatin is genotoxic and apoptogenic in non-tumour cells and the formation of reactive oxygen species appears to be responsible for these toxicities. The anti-genotoxic and anti-apoptotic effects of resveratrol, a polyphenol found in numerous plant species, against cisplatin-induced genotoxicity and apoptosis in vivo were evaluated by use of standard techniques in somatic and germinal cells of mice. Pre-treatment of mice with resveratrol significantly reduced cisplatin-induced genotoxicity and apoptosis and effectively suppressed the apoptotic signalling triggered by cisplatin. The protective effect of resveratrol was found to be stronger at the higher dose, indicating the dose-dependent effect of resveratrol. Cisplatin induced marked biochemical alterations characteristic of oxidative DNA stress. Prior administration of resveratrol before the cisplatin challenge ameliorated these biochemical markers. In conclusion, this study provides evidence for the first time that resveratrol has a protective role in the abatement of cisplatin-induced genotoxicity and apoptosis in somatic and germinal cells of mice. This activity resides, at least in part, in its radical scavenger activity. Therefore, resveratrol can be a promising chemoprotective agent to avert secondary malignancies and abnormal reproductive outcomes in cured cancer patients exposed to cisplatin, without diminishing its anti-neoplastic activity.     

Effects of organoselenium compound 2-(5-selenocyanato-pentyl)-benzo[de]isoquinoline 1,3-dione on cisplatin induced nephrotoxicity and genotoxicity: an investigation of the influence of the compound on oxidative stress and antioxidant enzyme system

Cisplatin is one of the most active cytotoxic agents used in the treatment of cancer. However, cisplatin therapy is also associated with severe side effects like nephrotoxicity and genotoxicity. Free oxygen radicals are known to play a major role in cisplatin induced toxicities. Selenium is believed to be an important trace element and dietary antioxidant because of its ability to scavenge free oxygen radicals, thereby preventing cells from oxidative stress. The purpose of this study is to evaluate the protective role of a novel naphthalimide based organoselenium compound 2-(5-selenocyanato-pentyl)-benzo[de]isoquinoline 1,3-dione against cisplatin induced toxicities in Swiss albino mice. Cisplatin was administered intraperitoneally (5 mg/kg b.w.) and the organoselenium compound was given by oral gavages (3 mg/kg b.w.) in concomitant and pretreatment schedule. The results showed that the test compound substantially reduced cisplatin induced reactive oxygen species generation and lipid peroxidation in kidney as well as blood urea nitrogen and creatinine levels in serum. Treatment with organoselenium compound was also able to restore the renal antioxidant system by modulating the cisplatin induced depleted activities of glutathione S-transferase, thioredoxin reductase, superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione level. In addition, the organoselenium compound could efficiently minimize cisplatin induced chromosomal aberrations in bone marrow cells and extent of DNA damage in lymphocytes. Furthermore, the chemoprotective efficacy of the compound against cisplatin induced toxicity was confirmed by histopathological evaluation. The results suggest that the organoselenium compound has the potential to protect against cisplatin induced nephrotoxicity and genotoxicity in part by scavenging reactive oxygen species and by up regulating the antioxidant enzyme system.     

The Antioxidant and Antigenotoxic Effects of Pycnogenol<Superscript>®</Superscript> on Rats Treated With Cisplatin

Oxidative stress and inflammation are implicated in the pathogenesis of cisplatin-induced toxicity. Pycnogenol® is known for its strong antioxidant and anti-inflammatory effects. In this study, the possible protective effects of pycnogenol on kidney, bone marrow, and red blood cells in rats treated with cisplatin were investigated. The rats were divided into four groups. Group 1 was the control and groups 2, 3, and 4 were orally treated with pycnogenol (200 mg/kg bw, o.p) for 5 days, treated with cisplatin (7 mg/kg bw, i.p.) on the fifth day and treated with cisplatin plus pycnogenol, respectively. Antioxidative parameters in kidney and red blood cells were measured. Chromosome anomalies in bone marrow and renal histopathology were also investigated. Activities of pro-oxidant enzymes (myeloperoxidase and xanthine oxidase), malondialdehyde, and nitric oxide levels significantly increased but antioxidant enzymes activities decreased in the kidneys and red blood cells after cisplatin treatment. Pycnogenol treatment prior to the administration of cisplatin significantly decreased cisplatin-induced injury, as evidenced by its normalizing these parameters. Chromosomal aberrations decreased and mitotic index frequencies increased in bone marrow treated with cisplatin plus pycnogenol. These findings suggest that pycnogenol may be a useful protective agent against the toxicity associated with cisplatin therapy.     

Effect of cisplatin on mitochondrial protein, glutathione, and succinate dehydrogenase in Dalton lymphoma-bearing mice

Cisplatin treatment of tumor-bearing mice resulted a significant decrease of protein in the tissues studied (liver, kidney, and Dalton lymphoma) and also in their mitochondrial fractions. As compared to respective tissues, the protein decrease was noted to be more conspicuous in their mitochondrial fractions. Similarly, mitochondrial glutathione also decreased significantly in the tissues. However, succinate dehydrogenase activity was selectively decreased in the kidney and Dalton lymphoma cells, whereas in liver it remained almost unchanged. An increase in serum urea concentration and kidney mitochondrial lipid peroxidation was also observed after cisplatin treatment. It is suggested that the cisplatin-induced biochemical changes in mitochondria involving mitochondrial protein, glutathione, and succinate dehydrogenase could be the important potent cellular sites contributing to toxicity/cytotoxicity after cisplatin treatment. This revised version was published online in July 2006 with corrections to the Cover Date.     

Cytogenetic studies in mice treated with the jet fuels, Jet-A and JP-8

The genotoxic potential of the jet fuels, Jet-A and JP-8, were examined in mice treated on the skin with a single dose of 240 mg/mouse. Peripheral blood smears were prepared at the start of the experiment (t = 0), and at 24, 48 and 72 h following treatment with jet fuels. Femoral bone marrow smears were made when all animals were sacrificed at 72 h. In both tissues, the extent of genotoxicity was determined from the incidence of micronuclei (MN) in polychromatic erythrocytes. The frequency of MN in the peripheral blood of mice treated with Jet-A and JP-8 increased over time and reached statistical significance at 72 h, as compared with concurrent control animals. The incidence of MN was also higher in bone marrow cells of mice exposed to Jet-A and JP-8 as compared with controls. Thus, at the dose tested, a small but significant genotoxic effect of jet fuels was observed in the blood and bone marrow cells of mice treated on the skin.     

Effect of cisplatin on Allium cepa root meristem cells

Allium cepa root growth was retarded by cisplatin treatment in a dose-dependent manner. A decrease in the mitotic index (MI) and an increase in the number of interphase cells was seen in cisplatin treated root tips. An increase in the frequency of abnormal mitoses and chromosomal aberrations was also observed in cisplatin treated groups which indicates its genotoxic effect on plant cells. The endogenous glutathione (GSH) level in the root tips decreased significantly after cisplatin treatment which may favour its increased interaction with cellular DNA thereby developing enhanced chromosomal aberrations and affecting cell divisions and root growth. It is suggested that the decrease in endogenous GSH may be related to the development of cisplatin-mediated genotoxic effects in plants.     

Protective effect of Hemidesmus indicus R.Br. root extract against cisplatin-induced cytogenetic damage in mouse bone marrow cells

The aqueous extract of Hemidesmus indicus roots was investigated for its in vivo antigenotoxic effect against cisplatin-induced cytogenetic damage. Swiss albino mice were administered with various doses of the extract either singly (50, 100 and 200 mg/kg body weight) or as split doses (10, 20 and 40 mg/kg bw/day) for five consecutive days by oral gavage. As endpoints, chromosome aberrations, micronuclei in polychromatic erythrocytes, mitotic index and PCE/NCE ratio were estimated. The extract protected the bone marrow cells from cisplatin-induced genotoxicity in an inverse dose-dependent manner. However, the extract was cytotoxic at all doses. But, under split dose regime it conferred a higher level of genoprotection and was not cytotoxic at the lower two doses. The presence of saponins, tannins, phenols, terpenoids, flavonoids and coumarins in the crude extract could explain these effects.     

Cytogenetic effects of a mixture of selected metals following subchronic exposure through drinking water in male rats

The current study examines the genotoxic effects of subchronic exposure via drinking water to a mixture of eight metals (arsenic, cadmium, lead, mercury, chromium, nickel, manganese and iron) found as contaminants of water sources in different parts of India and its possible association with oxidative stress. Male rats were exposed to the mixture at 0, 1, 10 and 100 times the mode concentration of each metal daily for 90 days. Another dose group at concentration equivalent to maximum permissible limit (MPL) for each metal and a reference group given ip cyclophosphamide were incorporated. The mixture at 100x level significantly increased chromosomal aberrations and micronuclei induction (2.4 folds) in bone marrow cells and reduced the ratio of polychromatic to normochromatic erythrocytes by 25%. The mixture significantly increased sister chromatid exchange in bone marrow (1.67 and 2.3 folds) and spleen (1.57 and 1.98 folds) cells with both 10x and 100x doses. Cyclophosphamide was more potent than the mixture in causing cytogenetic damage in these parameters. In rat spleen, the mixture at 10x and 100x doses caused dose-dependent increase in lipid peroxidation (25.95 and 52.71%) and decrease in the activities of superoxide dismutase (20.36 and 40.62%), catalase (18.24 and 35.50%), glutathione peroxidase (22.33 and 36.12%) and glutathione reductase (19.22 and 31.35%) and in the level of GSH (19.76 and 35.15%). The results suggest that the mixture induced genotoxicity in rat bone marrow and spleen cells at concentrations relatively higher than that found in groundwater sources and the genotoxic effect could relate to induction of oxidative stress. However, observations with lower doses indicate that additive or synergistic interactions following exposure to metal components at MPL levels or at mode concentrations of contemporary groundwater levels in India may not result in clastogenicity in male rats.     

Chromosomal abnormalities and sister-chromatid exchange in bone marrow cells of mice and Chinese hamsters after inhalation and intraperitoneal administration. II. Cyclophosphamide

The genotoxic effects of cyclophosphamide (CPP), a human and animal carcinogen requiring metabolic activation, were studied in bone marrow cells of mice and Chinese hamsters, analyzing chromosome abnormalities (CA) and sister-chromatid exchange (SCE) after a 2-h inhalation or a single intraperitoneal administration. In order to compare the genotoxicity after the different routes of administration in the dose range of 10-110 mg CPP/kg body weight, the systemic dose obtained by inhalation was calculated from blood concentrations and the inhalation duration after an analysis of the CPP blood kinetics. In NMRI mice the frequency of bone marrow cells with chromosome abnormalities was higher after aerosol exposure than after intraperitoneal administration of comparable CPP doses. In Chinese hamsters the CA frequency was similar with both exposure routes. Inhaled CPP was found to induce a higher frequency of CA and SCE in the bone marrow cells of mice compared to those of Chinese hamsters. The findings suggest that for genotoxins requiring metabolic activation species differences exist with respect to the influence of the route of entry and the sensitivity of bone marrow cells.     

Micronuclei in peripheral blood and bone marrow cells of mice exposed to 42 GHz electromagnetic millimeter waves

The genotoxic potential of 42.2 +/- 0.2 GHz electromagnetic millimeter-wave radiation was investigated in adult male BALB/c mice. The radiation was applied to the nasal region of the mice for 30 min/day for 3 consecutive days. The incident power density used was 31.5 +/- 5.0 mW/cm2. The peak specific absorption rate was calculated as 622 +/- 100 W/kg. Groups of mice that were injected with cyclophosphamide (15 mg/kg body weight), a drug used in the treatment of human malignancies, were also included to determine if millimeter-wave radiation exposure had any influence on drug-induced genotoxicity. Concurrent sham-exposed and untreated mice were used as controls. The extent of genotoxicity was assessed from the incidence of micronuclei in polychromatic erythrocytes of peripheral blood and bone marrow cells collected 24 h after treatment. The results indicated that the incidence of micronuclei in 2000 polychromatic erythrocytes was not significantly different among untreated, millimeter wave-exposed, and sham-exposed mice. The group mean incidences were 6.0 +/- 1.6, 5.1 +/- 1.5 and 5.1 +/- 1.3 in peripheral blood and 9.1 +/- 1.1, 9.3 +/- 1.6 and 9.1 +/- 1.6 in bone marrow cells, respectively. Mice that were injected with cyclophosphamide exhibited significantly increased numbers of micronuclei, 14.6 +/- 2.7 in peripheral blood and 21.3 +/- 3.9 in bone marrow cells (P< 0.0001). The drug-induced micronuclei were not significantly different in millimeter wave-exposed and sham-exposed mice; the mean incidences were 14.3 +/- 2.8 and 15.4 +/- 3.0 in peripheral blood and 23.5 +/- 2.3 and 22.1 +/- 2.5 in bone marrow cells, respectively. Thus there was no evidence for the induction of genotoxicity in the peripheral blood and bone marrow cells of mice exposed to electromagnetic millimeter-wave radiation. Also, millimeter-wave radiation exposure did not influence cyclophosphamide-induced micronuclei in either type of cells.     

The in vivo genotoxicity of cisplatin,isoflurane and halothane evaluated by alkaline comet assay in Swiss albino mice

The aim of this study was to evaluate the genotoxicity of repeated exposure to isoflurane or halothane and compare it with the genotoxicity of repeated exposure to cisplatin. We also determined the genotoxicity of combined treatment with inhalation anaesthetics and cisplatin on peripheral blood leucocytes (PBL), brain, liver and kidney cells of mice. The mice were divided into six groups as follows: control, cisplatin, isoflurane, cisplatin–isoflurane, halothane and cisplatin–halothane, and were exposed respectively for three consecutive days. The mice were treated with cisplatin or exposed to inhalation anaesthetic; the combined groups were exposed to inhalation anaesthetic after treatment with cisplatin. The alkaline comet assay was performed. All drugs had a strong genotoxicity (P < 0.05 vs. control group) in all of the observed cells. Isoflurane caused stronger DNA damage on the PBL and kidney cells, in contrast to halothane, which had stronger genotoxicity on brain and liver cells. The combination of cisplatin and isoflurane induced lower genotoxicity on PBL than isoflurane alone (P < 0.05). Halothane had the strongest effect on brain cells, but in the combined treatment with cisplatin, the effect decreased to the level of cisplatin alone. Halothane also induced the strongest DNA damage of the liver cells, while the combination with cisplatin increased its genotoxicity even more. The genotoxicity of cisplatin and isoflurane on kidney cells were nearly at the same level, but halothane caused a significantly lower effect. The combinations of inhalation anaesthetics with cisplatin had stronger effects on kidney cells than inhalation anaesthetics alone. The observed drugs and their combinations induced strong genotoxicity on all of the mentioned cells.     

Effects of the antioxidants curcumin and vitamin C on cisplatin-induced clastogenesis in Wistar rat bone marrow cells

The use of dietary antioxidants to prevent antitumor agent-induced chromosomal damage in nontumor cells is currently eliciting considerable interest. Curcumin (CMN) is a dietary antioxidant that has been reported to protect against clastogenesis in in vivo and in vitro assays. This study was undertaken to investigate the modulatory effects of CMN on cisplatin-induced chromosomal aberrations in Wistar rat bone marrow cells and whether there is any potentiation of these effects with the combination between CMN and vitamin C (VC), which has been reported to reduce the clastogenic effect of many antitumor agents in in vivo assays. Animals treated with CMN plus a single dose of cisplatin, at 18, 24 or 72 h following treatment, presented a statistically significant reduction in the total amount of chromosomal damage and in the number of abnormal metaphases. The results also indicate that the combination between antioxidants would not be effective in protecting against cisplatin-induced chromosomal damage in animals sacrificed 24 h after cisplatin treatment. Under the present experimental conditions, CMN could prevent cisplatin-induced clastogenesis by acting as a free radical scavenger.     

Induction of micronuclei by Zearalenone in Vero monkey kidney cells and in bone marrow cells of mice: protective effect of Vitamin E

Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin mainly produced by Fusarium graminaerum, found as a world-wide contaminant mainly of corn and wheat. Previous studies have demonstrated that among several other effects on animals and humans, ZEN also displays hepatotoxicity, immunotoxicity and nephrotoxicity. ZEN is mainly known as a hormonal disrupter due to its estrogenic activities and consequent toxicity for reproduction. Furthermore, mutagenic and genotoxic proprieties of ZEN were disclosed recently, the molecular mechanisms of which are not yet well understood. In the present study, the genotoxic potential of ZEN was evaluated using genotoxicity tests: the 'cytokinesis block micronucleus assay' in Vero monkey kidney cells and the 'in vivo mouse bone marrow micronucleus assay'. In cultured cells treated with 5, 10 and 20 microM ZEN, the frequency of binucleated micronucleated cells (BNMN) was assessed in 1000 binucleated cells and in mice given oral doses of 10, 20 and 40 mg/kg bw, the frequency of polychromatic erythrocytes micronucleated (PCEMN) in bone marrow cells was assessed in 2000 polychromatic erythrocytes (PCE). The potential prevention of ZEN-induced effects by 25 microM Vitamin E (Vit E) was also evaluated.In vivo, doses of 10, 20 and 40 mg/kg bw ZEN representing, respectively 2, 4 and 8% of the LD50 (LD50 of ZEN in mice is 500 mg/kg bw), were administered to animals either with or without pre-treatment with Vit E (216.6 mg/kg bw) in order to evaluate its preventive potential.ZEN was found to induce micronuclei (MN) in a dose-dependent manner in cultured Vero cells as well as in mouse bone marrow cells. The present data emphasise the likely clastogenic pathway among the molecular mechanisms that underlay the ZEN-induced genotoxicity. Vit E was found to prevent partially-from 30 to 50%-these toxic effects, most likely acting either as a structural analogue of ZEN or as an antioxidant.     

TLR2 protects cisplatin-induced acute kidney injury associated with autophagy via PI3K/Akt signaling pathway

Toll-like receptors (TLRs), which are essential components of the innate immune response, play an important role in acute kidney injury (AKI). Toll-like receptor 2 (TLR2) is constitutively expressed in tubular epithelial cells of the kidney and participates in cisplatin-induced AKI. The autophagy is a dynamic catabolic process that maintains intracellular homeostasis, which is involved in the pathogenesis of AKI. Recent studies demonstrate that PI3K/Akt signaling pathway regulates autophagy in response to various stimuli. Therefore, we propose that cisplatin might activate TLR2, which subsequently phosphorylates PI3K/Akt, leading to enhanced autophagy of renal tubular epithelial cells and protecting cisplatin-induced AKI. We found that TLR2 expression was significantly increased in the kidney after the cisplatin treatment. TLR2-deficient mice exacerbated renal injury in cisplatin-induced AKI, with higher serum creatinine and blood urea nitrogen, more severe morphological injury compared with that of wild-type mice. In vitro, we found that inhibition of TLR2 reduced tubular epithelial cell autophagy after the cisplatin treatment. Mechanistically, TLR2 inhibited autophagy via activating PI3K/Akt signaling pathway in renal tubular epithelial cells after the cisplatin treatment. Take together, these results suggest that TLR2 may protect cisplatin-induced AKI by activating autophagy via PI3K/Akt signaling pathway.     

Genotoxicity and mutagenicity of Rosmarinus officinalis (Labiatae) essential oil in mammalian cells in vivo

Rosmarinus officinalis (rosemary) oil is widely used by the cosmetic, food, and pharmaceutical industries as a fragrance component of soaps, creams, lotions, and perfumes. Although it is popular, potential harmful side-effects of the oil have been described. We investigated the genotoxic and mutagenic potential of essential oil of R. officinalis in rodents, using comet, micronucleus and chromosome aberration assays. The animals were treated by gavage with one of three dosages of rosemary oil (300, 1000 or 2000 mg/kg). Liver and peripheral blood cells were collected from Swiss mice 24 h after treatment for the comet assay (genotoxicity endpoint), along with bone marrow cells for the micronucleus test (mutagenicity endpoint). Bone marrow cells were collected from Wistar rats 24 h after oil treatment for the micronucleus and chromosome aberration assays. Based on the comet assay, all three doses of rosemary oil induced significant increases in DNA damage in the mouse cells. There was a significant increase in micronucleated cells and chromosome aberrations only at the two higher doses. We conclude that rosemary essential oil provokes genotoxic and mutagenic effects when administered orally.     

Genotoxicity studies with pure trans-capsaicin

Both positive and negative effects have been found in classical genetic toxicology assays with capsaicin. However, the capsaicin tested in most studies has been derived from pepper plant extracts, which is likely to display varying degrees of purity and possibly diverse impurity profiles. Therefore, the objective of the series of studies reported here was to test the genotoxic potential of pure, synthetic trans-capsaicin (the only naturally occurring geometric isomer of capsaicin), using four genotoxicity assays widely used to evaluate drug substances. These included the Ames, mouse lymphoma cell mutation, mouse in vivo bone marrow micronucleus and chromosomal aberration in human peripheral blood lymphocytes (HPBL) assays. In the Ames assay, pure trans-capsaicin was not mutagenic to Salmonella typhimurium or Escherichia coli when dissolved in dimethylsulfoxide and tested at concentrations extending into the toxic range. trans-Capsaicin was weakly mutagenic in mouse lymphoma L5178Y cells, in the presence of S9 mix, when dissolved in dimethylsulfoxide and tested at concentrations extending into the toxic range. Limited evidence for very weak activity was also obtained in the absence of S9 mix. trans-Capsaicin did not induce micronuclei in bone marrow cells when tested to the maximum tolerated dose of 800 mg/kg per day in male and 200 mg/kg per day in female CD-1 mice using a 0 h plus 24 h oral dosing and 48 h sampling regimen. Finally, trans-capsaicin did not induce structural or numerical chromosomal aberrations when evaluated for its ability to induce clastogenicity in blood lymphocytes. Taken together, these data suggest that the genotoxic potential of pure trans-capsaicin is very low, especially as the clinical significance of weak mutagenicity in the mouse lymphoma assay for catechol-moiety containing compounds is unclear. Moreover, the different genotoxicity profiles of pure trans-capsaicin and purified chili pepper extracts suggest that the purity and source of capsaicin should always be an important consideration for toxicological evaluations.     

Amelioration of cisplatin-induced nephrotoxicity in mice by oral administration of diphenylmethyl selenocyanate

Cisplatin is one of the most potent and active cytotoxic drug in the treatment of cancer. However, side-effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the promising efficacy of cisplatin. The present study was designed to ascertain the possible in vivo protective potential of a synthetic organoselenium compound diphenylmethyl selenocyanate (3 mg/kg.b.w.) against the nephrotoxic damage induced by cisplatin (5 mg/kg.b.w. for 5 days) in Swiss albino mice. Treatment with diphenylmethyl selenocyanate markedly reduced cisplatin-induced lipid peroxidation, serum creatinine and blood urea nitrogen levels. Renal antioxidant defense systems, such as glutathione-S-transferase, glutathione peroxidase, superoxide dismutase, catalase, activities and reduced glutathione level, depleted by cisplatin therapy, were restored to normal by the selenium compound. The selenium compound also reduced renal tubular epithelial cell damage, nitric oxide levels and expression of COX-2, and iNOS in kidneys injured by cisplatin. These results demonstrate the protective effect of diphenylmethyl selenocyanate against cisplatin-induced nephrotoxicity in mice.     

Role of CFTR in oxidative stress and suicidal death of renal cells during cisplatin-induced nephrotoxicity

The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl⁻ channel not only involved in chloride secretion but as well in glutathione (GSH) transport. Thus, we tested whether the inhibition of CFTR could protect against cisplatin-induced nephrotoxicity. Using a renal proximal cell line, we show that the specific inhibitor of CFTR, CFTR_inh-172, prevents cisplatin-induced cell death and apoptosis by modulating the intracellular reactive oxygen species balance and the intracellular GSH concentration. This CFTR_inh-172-mediated protective effect occurs without affecting cellular cisplatin uptake or the formation of platinum-DNA adducts. The protective effect of CFTR_inh-172 in cisplatin-induced nephrotoxicity was also investigated in a rat model. Five days after receiving a single cisplatin injection (5 mg/kg), rats exhibited renal failure, as evidenced by the alteration of biochemical and functional parameters. Pretreatment of rats with CFTR_inh-172 (1 mg/kg) prior to cisplatin injection significantly prevented these deleterious cisplatin-induced nephrotoxic effects. Finally, we demonstrate that CFTR_inh-172 does not impair cisplatin-induced cell death in the cisplatin-sensitive A549 cancer cell line. In conclusion, the use of a specific inhibitor of CFTR may represent a novel therapeutic approach in the prevention of nephrotoxic side effects during cisplatin treatment without affecting its antitumor efficacy.