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
• Názvy látek
• cisplatina MeSH
• měď MeSH
• platina MeSH
• železo MeSH
• zinek MeSH

Changes in zinc content and dysregulated zinc homeostatic mechanisms have been recognized in several solid malignancies such as prostate cancer, breast cancer, or pancreatic cancer. Moreover, it has been shown that zinc serum and/or tissue levels are altered in melanoma with varying effects on melanoma development and biology. This study was conducted to explore the effects of acute increases of intracellular zinc in a set of melanoma tissue explants obtained from clinical samples. Measurements of their zinc content showed an extant heterogeneity in total and free intracellular zinc pools associated with varying biological behavior of individual cells, e.g., autophagy levels and propensity to cell death. Use of zinc pyrithione elevated intracellular zinc in a short time frame which resulted in marked changes in mitochondrial activity and lysosomes. These alterations were accompanied by significantly enhanced autophagy flux and subsequent cell demise in the absence of typical apoptotic cell death markers. The present results show for the first time that acutely increased intracellular zinc in melanoma cells specifically enhances their autophagic activity via mitochondria and lysosomes which leads to autophagic cell death. While biologically relevant, this discovery may contribute to our understanding and exploration of zinc in relation to autophagy as a means of controlling melanoma growth and survival.

• Klíčová slova
• autophagy, cell death, lysosomes, melanoma, mitochondria, zinc,
• MeSH
• apoptóza MeSH
• autofagie * účinky léků   MeSH
• buněčná smrt MeSH
• časové faktory MeSH
• intracelulární membrány účinky léků   metabolismus   MeSH
• intracelulární prostor metabolismus   MeSH
• lidé MeSH
• lyzozomy metabolismus   MeSH
• melanocyty účinky léků   metabolismus   MeSH
• melanom metabolismus   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• nádorové buněčné linie MeSH
• proliferace buněk MeSH
• zinek metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• zinek MeSH

National cancer databases document that melanoma is the most aggressive and deadly cutaneous malignancy with worldwide increasing incidence in the Caucasian population. Around 10% of melanomas occur in families. Several germline mutations were identified that might help to indicate individuals at risk for preventive interventions and early disease detection. More than 50% of sporadic melanomas carry mutations in Ras/Raf/mitogen-activated protein kinase (MAPK/MEK) pathway, which may represent aims of novel targeted therapies. Despite advances in targeted therapies and immunotherapies, the outcomes in metastatic tumor are still unsatisfactory. Here, we review animal models that help our understanding of melanoma development and treatment, including non-vertebrate, mouse, swine, and other mammal models, with an emphasis on those with spontaneously developing melanoma. Special attention is paid to the melanoma-bearing Libechov minipig (MeLiM). This original swine model of hereditary metastatic melanoma enables studying biological processes underlying melanoma progression, as well as spontaneous regression. Current histological, immunohistochemical, biochemical, genetic, hematological, immunological, and skin microbiome findings in the MeLiM model are summarized, together with development of new therapeutic approaches based on tumor devitalization. The ongoing study of molecular and immunological base of spontaneous regression in MeLiM model has potential to bring new knowledge of clinical importance.

• Klíčová slova
• MeLiM, animal model, devitalization, genetics, melanoma, mutation, progression, spontaneous regression, swine,
• MeSH
• maligní melanom kůže MeSH
• melanom genetika   MeSH
• miniaturní prasata genetika   MeSH
• modely nemocí na zvířatech MeSH
• nádory kůže genetika   MeSH
• prasata genetika   MeSH
• progrese nemoci MeSH
• sekundární malignity genetika   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

BACKGROUND: Treatment of advanced cutaneous melanoma remains challenging, and new data on melanoma biology are required. The most widely accepted criteria for the prognostic evaluation of melanoma are histopathological and clinical parameters, and the identification of additional tumor markers is thus of paramount importance. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI), an important tool in cancer research, is useful for unraveling the molecular profile of melanoma. METHODOLOGY/PRINCIPAL FINDINGS: In this report, we used the melanoma-bearing Libechov minipig (MeLiM), a unique animal model that allows observation of the complete spontaneous regression of invasive cutaneous melanoma, to investigate i) the differences between melanoma and healthy skin protein profiles and ii) the proteins potentially involved in spontaneous regression. The MeLiM tissues were cryosected, histologically characterized, analyzed by MALDI MSI, and immunohistologically stained. Multivariate statistical analyses of the MALDI MSI data revealed ten relevant m/z ions, of which the expression levels varied significantly among the studied MeLiM tissues. These ion peaks were used to create mass ion images/maps and visualize the differences between tumor and healthy skin specimens, as well as among histologically characterized tissue regions. CONCLUSIONS/SIGNIFICANCE: Protein profiles comprising ten statistically significant mass ion peaks useful for differentiating cutaneous melanoma and healthy skin tissues were determined. Peaks at m/z 3044, 6011, 6140 and 10180 were overexpressed in melanoma compared with healthy skin tissue. More specifically, m/z 6140 was expressed at significantly (p < 0.05) higher levels in normally growing melanoma regions than in regions with early and late spontaneous regression. This study demonstrates the clinical utility of MALDI MSI for the analysis of tissue cryosections at a molecular level.

• MeSH
• melanom metabolismus   patologie   MeSH
• nádorové proteiny metabolismus   MeSH
• prasata MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice metody   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorové proteiny MeSH