The main dose-limiting side effect of cisplatin is nephrotoxicity. The utilization of cisplatin is an issue of balancing tumour toxicity versus platinum-induced nephrotoxicity. In this study, we focused on intraorgan distribution of common essential trace elements zinc, copper, and iron in healthy mouse kidneys and distribution of platinum after cisplatin treatment. Renal distribution in 12 nontreated Nu-Nu mice (males) was assessed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). Furthermore, 9 Nu-Nu mice were treated with cisplatin. The order of elements concentration in kidneys was as follows: Fe > Zn > Cu. All three metals showed the higher concentrations at the cortex and medulla (28.60, 3.35, and 93.83 μg/g for Zn, Cu, and Fe, respectively) and lower concentration at the pelvis and the urinary tract (20.20, 1.93, and 62.48 μg/g for Zn, Cu, and Fe, respectively). No statistically significant difference between cortex and medulla was observed for these elements. After platinum treatment, the concentration of platinum in kidneys was enhanced more than 60-times, p < 0.001. Platinum significantly showed the highest accumulation in cortex (2.11 μg/g) with a gradient distribution. Platinum was less accumulated in medulla and pelvis than in cortex, and the lowest accumulation occurred in the urinary tract (1.13 μg/g). Image processing has been successfully utilized to colocalize metal distribution using LA-ICP-MS and histological samples images.
- MeSH
- buňky PC-3 MeSH
- cisplatina škodlivé účinky farmakologie toxicita MeSH
- hmotnostní spektrometrie metody MeSH
- ledviny účinky léků metabolismus patologie MeSH
- lidé MeSH
- měď analýza MeSH
- myši nahé MeSH
- myši MeSH
- platina analýza MeSH
- spektrální analýza metody MeSH
- železo analýza MeSH
- zinek analýza MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The human proximal tubular HK-2 cell line is an immortalized cell line commonly used for studying proximal tubular toxicity. Even as their use is presently increasing, there unfortunately are no studies focused on functional changes in HK-2 cells associated with passaging. The aim of the present study, therefore, was to evaluate the functional stability of HK-2 cells during 13 weeks of continuous passaging after 6 and 24 h of treatment with model nephrotoxic compounds (i.e., acetaminophen, cisplatin, CdCl(2)). Short tandem repeat profile, the doubling time, cell diameter, glutathione concentration, and intracellular dehydrogenase activity were measured in HK-2 cells at each tested passage. The results showed that HK-2 cells exhibit stable morphology, cell size, and cell renewal during passaging. Mean doubling time was determined to be 54 h. On the other hand, we observed a significant effect of passaging on the susceptibility of HK-2 cells to toxic compounds. The largest difference in results was found in both cadmium and cisplatin treated cells across passages. We conclude that the outcomes of scientific studies on HK-2 cells can be affected by the number of passages even after medium-term cultivation and passaging for 13 weeks.
- MeSH
- antitumorózní látky toxicita MeSH
- buněčné kultury metody MeSH
- buněčné linie MeSH
- cisplatina toxicita MeSH
- kadmium toxicita MeSH
- lidé MeSH
- neopioidní analgetika toxicita MeSH
- paracetamol toxicita MeSH
- proximální tubuly ledvin účinky léků patologie MeSH
- viabilita buněk MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
PR domain containing 9 (Prdm9) is specifying hotspots of meiotic recombination but in hybrids between two mouse subspecies Prdm9 controls failure of meiotic chromosome synapsis and hybrid male sterility. We have previously reported that Prdm9-controlled asynapsis and meiotic arrest are conditioned by the inter-subspecific heterozygosity of the hybrid genome and we presumed that the insufficient number of properly repaired PRDM9-dependent DNA double-strand breaks (DSBs) causes asynapsis of chromosomes and meiotic arrest (Gregorova et al., 2018). We now extend the evidence for the lack of properly processed DSBs by improving meiotic chromosome synapsis with exogenous DSBs. A single injection of chemotherapeutic drug cisplatin increased frequency of RPA and DMC1 foci at the zygotene stage of sterile hybrids, enhanced homolog recognition and increased the proportion of spermatocytes with fully synapsed homologs at pachytene. The results bring a new evidence for a DSB-dependent mechanism of synapsis failure and infertility of intersubspecific hybrids.
- MeSH
- antitumorózní látky toxicita MeSH
- cisplatina toxicita MeSH
- dvouřetězcové zlomy DNA účinky léků MeSH
- histonlysin-N-methyltransferasa genetika metabolismus MeSH
- hybridizace genetická MeSH
- meióza účinky léků genetika MeSH
- mužská infertilita genetika MeSH
- myši inbrední C57BL MeSH
- oprava DNA MeSH
- párování chromozomů účinky léků genetika MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Ateroskleróza vyvolaná konvenčnými protinádorovými liekmi a rádioterapiou je známym problémom onkologických pacientov. K novším kardiotoxickým liekom používaným u týchto pacientov patrí cielená terapia a medikamentózna androgén deprivačná liečba, ktoré tiež môžu indukovať vaskulárne poškodenie. Najnovšiu skupinu kardiotoxických antineoplastických látok používaných u onkologických pacientov predstavujú inhibítory imunitných kontrolných bodov. V predkladanom článku poukazujeme na recentné údaje týkajúce sa aterosklerotického poškodenia navodeného rádioterapiou a vybranými dôležitými liekmi často používanými v onkológii. Článok sa venuje aj spoločným rizikovým faktorom onkologických ochorení a aterosklerózy a tiež zápalu indukovanému malignitou.
Atherosclerosis induced by conventional anticancer drugs and radiotherapy have been a relevant issue of cancer patients during last decade. In addition, targeted and androgen-deprivation therapies can also induce vascular damage in these patients. Immune checkpoint inhibitors are a novel class of effective antineoplastic drugs with cardiotoxicity used in patients with malignancies. Atherosclerotic damage has been long underestimated in clinical practice, but recently a significant number of patients with serious artery disease during or after completion of anticancer therapy have been reported. Here we describe atherosclerosis induced by selected prominent drugs and radiotherapy used in oncology which have received particular attention in recent years. Additionally, this article presents common risk factors for cancer and atherosclerosis. It deals also with inflammation triggered by cancer.
- MeSH
- antitumorózní látky toxicita MeSH
- ateroskleróza * etiologie farmakoterapie chemicky indukované MeSH
- cisplatina terapeutické užití toxicita MeSH
- kardiotoxicita MeSH
- kardiovaskulární nemoci chemicky indukované MeSH
- lidé MeSH
- nádory * terapie MeSH
- radioterapie škodlivé účinky MeSH
- rizikové faktory MeSH
- zánět MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Neutrophil gelatinase-associated lipocalin is an extracellular protein produced mostly in kidney. Recently, it has become a promising biomarker of renal damage in vivo. On the other hand, the validation of NGAL as a biomarker for nephrotoxicity estimation in vitro has not been characterized in detail yet. Since the HK-2 cells are frequently used human kidney cell line, we aimed to characterize the production of NGAL in these cells and to evaluate NGAL as a possible marker of cell impairment. We used heavy metals (mercury, cadmium), peroxide, drugs (acetaminophen, gentamicin) and cisplatin to mimic nephrotoxicity. HK-2 cells were incubated with selected compounds for 1-24h and cell viability was measured together with extracellular NGAL production. We proved that HK-2 cells possess a capacity to produce NGAL in amount of 2pg/ml/h. We found a change in cell viability after 24h incubation with all tested toxic compounds. The largest decrease of the viability was detected in mercury, acetaminophen, cisplatin and gentamicin. Unexpectedly, we found also a significant decrease in NGAL production in HK-2 cells treated with these toxins for 24h: to 11±5%, 54±5%, 57±6% and 76±9% respectively, compared with controls (=100%). Our results were followed with qPCR analysis when we found no significant increase in LCN2 gene expression after 24h incubation. We conclude that extracellular NGAL production negatively correlates with HK-2 cell impairment.
- MeSH
- akutní poškození ledvin chemicky indukované metabolismus MeSH
- biologické markery metabolismus MeSH
- buněčné linie MeSH
- cisplatina toxicita MeSH
- gentamiciny toxicita MeSH
- kadmium toxicita MeSH
- lidé MeSH
- lipokalin-2 genetika metabolismus MeSH
- paracetamol toxicita MeSH
- rtuť toxicita MeSH
- terc-butylhydroperoxid toxicita MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- aminoglykosidy škodlivé účinky MeSH
- antihypertenziva škodlivé účinky MeSH
- antitumorózní látky škodlivé účinky MeSH
- cisplatina škodlivé účinky toxicita MeSH
- gentamiciny škodlivé účinky toxicita MeSH
- lékové interakce MeSH
- lidé MeSH
- nežádoucí účinky léčiv * diagnóza etiologie komplikace MeSH
- polékové dyskineze diagnóza etiologie komplikace MeSH
- polypharmacy MeSH
- psychotropní léky škodlivé účinky MeSH
- somatosenzorické poruchy diagnóza etiologie MeSH
- vertigo * diagnóza etiologie MeSH
- vestibulární aparát * účinky léků MeSH
- závrať diagnóza etiologie MeSH
- Check Tag
- lidé MeSH
In this study, the pyrrolo[2,1-a]isoquinolines 4a-n were synthesized in good yields in a three steps synthesis from the corresponding α,β-unsaturated esters starting materials. These compounds were tested on six human cancer cells lines to measure the cytotoxic activity as a function of the electronic properties and aromaticity of the substituent at the C-2 position of the pyrroloisoquinoline. Our results reveal that the cytotoxic activity could be explained in terms of the distribution of electronic density across the ring joined to C-2. Also, this study identified 3-hydroxy (4d) and 3-chloro (4j) derivatives with powerful cytotoxic activities. The IC50 values of these compounds were found to be comparable to those of the commercially available Topotecan, Irinotecan, Etoposide, Tamoxifen, and Cisplatin.
- MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- cisplatina toxicita MeSH
- isochinoliny chemie farmakologie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- pyrroly chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Fluorometric glutathione assays have been generally preferred for their high specificity and sensitivity. An additional advantage offered by fluorescent bimane dyes is their ability to penetrate inside the cell. Their ability to react with glutathione within intact cells is frequently useful in flow cytometry and microscopy. Hence, the aims of our study were to use monochlorobimane for optimizing a spectrofluorometric glutathione assay in cells and then to compare that assay with the frequently used ortho-phthalaldehyde assay. We used glutathione-depleting agents (e.g., cisplatin and diethylmalonate) to induce cell impairment. For glutathione assessment, monochlorobimane (40μM) was added to cells and fluorescence was detected at 394/490nm. In addition to the regularly used calculation of glutathione levels from fluorescence change after 60min, we used an optimized calculation from the linear part of the fluorescence curve after 10min of measurement. We found that 10min treatment of cells with monochlorobimane is sufficient for evaluating cellular glutathione concentration and provides results entirely comparable with those from the standard ortho-phthalaldehyde assay. In contrast, the results obtained by the standardly used evaluation after 60min of monochlorobimane treatment provided higher glutathione values. We conclude that measuring glutathione using monochlorobimane with the here-described optimized evaluation of fluorescence signal could be a simple and useful method for routine and rapid assessment of glutathione within intact cells in large numbers of samples.
- MeSH
- biotest ekonomika metody MeSH
- buněčné linie MeSH
- cisplatina toxicita MeSH
- fluorescenční barviva chemie MeSH
- fluorescenční spektrometrie ekonomika metody MeSH
- glutathion analýza metabolismus MeSH
- lidé MeSH
- malonáty toxicita MeSH
- o-ftalaldehyd chemie MeSH
- průtoková cytometrie MeSH
- pyrazoly chemie MeSH
- senzitivita a specificita MeSH
- studie proveditelnosti MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- cetuximab terapeutické užití toxicita účinky léků MeSH
- cisplatina škodlivé účinky terapeutické užití toxicita MeSH
- imunoterapie * MeSH
- klinická studie jako téma MeSH
- kombinovaná farmakoterapie MeSH
- kvalita života MeSH
- lidé MeSH
- nádory hlavy a krku * farmakoterapie chirurgie radioterapie sekundární MeSH
- nivolumab aplikace a dávkování terapeutické užití MeSH
- protokoly protinádorové léčby MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Cisplatin is one of the most potent chemotherapy drugs against cancer, but its major side effect such as nephrotoxicity limits its use. Inhibition of poly(ADP-ribose) polymerase (PARP) protects against various renal diseases via gene transactivation and/or ADP-ribosylation. However, the role of PARP in necrotic cell death during cisplatin nephrotoxicity remains an open question. Here we demonstrated that pharmacological inhibition of PARP by postconditioning dose-dependently prevented tubular injury and renal dysfunction following cisplatin administration in mice. PARP inhibition by postconditioning also attenuated ATP depletion during cisplatin nephrotoxicity. Systemic release of high mobility group box 1 (HMGB1) protein in plasma induced by cisplatin administration was significantly diminished by PARP inhibition by postconditioning. In in vitro kidney proximal tubular cell lines, PARP inhibition by postconditioning also diminished HMGB1 release from cells. These data demonstrate that cisplatin-induced PARP1 activation contributes to HMGB1 release from kidney proximal tubular cells, resulting in the promotion of inflammation during cisplatin nephrotoxicity.
- MeSH
- akutní poškození ledvin chemicky indukované metabolismus MeSH
- antitumorózní látky toxicita MeSH
- cisplatina toxicita MeSH
- ledvinové kanálky účinky léků metabolismus sekrece MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- poly-ADP-ribóza-polymeráza 1 metabolismus MeSH
- protein HMGB1 sekrece MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
