Organic anion transporter polypeptides (OATPs) mediate the transmembrane uptake of endogenous compounds and clinically important drugs in various tissues thereby effecting drug disposition and tissue penetration. OATPs have also been identified in gastric, pancreatic and colon carcinomas but little is known about their expression in breast carcinoma. We therefore analyzed the expression pattern of all 11 known OATPs in three breast cancer cell lines (MCF-7, ZR-75-1, MDA-MB-231) and one immortalized breast epithelial cell line (MCF-10A) using quantitative real-time RT-PCR. Transcripts of 7/11 OATP genes with heterogeneity in their expression profile were detected in control and/or cancer cell lines. Of these seven OATPs, five were also expressed in breast tumor and adjacent non-tumorous specimens from 13 patients. OATP2B1, not found in the analyzed cell lines, was verified in the tissue samples. Interestingly, mRNA expression of OATP2B1, OPATP3A1 and OATP4A1 was significantly higher (p < 0.022) in non-malignant specimens as compared to tumor tissue samples.
Members of the organic anion transporter family (OATP) mediate the transmembrane uptake of clinical important drugs and hormones thereby affecting drug disposition and tissue penetration. Particularly OATP subfamily 1 is known to mediate the cellular uptake of anticancer drugs (e.g., methotrexate, derivatives of taxol and camptothecin, flavopiridol, and imatinib). Tissue-specific expression was shown for OATP1B1/OATP1B3 in liver, OATP4C1 in kidney, and OATP6A1 in testis, while other OATPs, for example, OATP4A1, are expressed in multiple cells and organs. Many different tumor entities show an altered expression of OATPs. OATP1B1/OATP1B3 are downregulated in liver tumors, but highly expressed in cancers in the gastrointestinal tract, breast, prostate, and lung. Similarly, testis-specific OATP6A1 is expressed in cancers in the lung, brain, and bladder. Due to their presence in various cancer tissues and their limited expression in normal tissues, OATP1B1, OATP1B3, and OATP6A1 could be a target for tumor immunotherapy. Otherwise, high levels of ubiquitous expressed OATP4A1 are found in colorectal cancers and their metastases. Therefore, this OATP might serve as biomarkers for these tumors. Expression of OATP is regulated by nuclear receptors, inflammatory cytokines, tissue factors, and also posttranslational modifications of the proteins. Through these processes, the distribution of the transporter in the tissue will be altered, and a shift from the plasma membrane to cytoplasmic compartments is possible. It will modify OATP uptake properties and, subsequently, change intracellular concentrations of drugs, hormones, and various other OATP substrates. Therefore, screening tumors for OATP expression before therapy should lead to an OATP-targeted therapy with higher efficacy and decreased side effects.
Eleven members of the human organic anion transporter (OATP) family (grouped into six families) facilitate the Na(+)- independent transmembrane transport of various endo- and xenobiotics (bile acids, bilirubin, steroid hormone conjugates, thyroid hormones, prostaglandins, clinically used drugs, and toxins). OATPs are 12-transmembrane glycoproteins (643-722 amino acids) and contain many conserved structural features, for example, eleven cysteines in the large extracellular loop 5. They are important for proper transport, for which translocation of substrates through a central, positively-charged pore in a rocker-switch-type mechanism has been proposed. Although OATPs are expressed in various cells and tissues, some members show a more restricted pattern (well-studied OATP1B1/OATP1B3 in liver, OATP4C1 in kidney, and OATP6A1 in testis). In cancer, the distribution pattern is no longer maintained, and OATPs, like OATP1B3, become upregulated in malignant tissues (colon, breast, prostate). Studies in cell lines and animal models further revealed that the expression of OATPs is regulated in a cell- and tissue-specific way by cytokines and activation of nuclear receptors (LXR, FXR, PXR, CAR, HNF4). Also epigenetic mechanisms and postranslational modifications influence their expression and function. Therefore, changes in the expression of OATPs under pathological conditions will influence transport processes causing an altered accumulation of OATP substrates in cells of excretory organs (intestine, liver, kidney) and on various blood/organ barriers (such as brain, testis, placenta). For drugs, this may result in increased toxicity and adverse drug reactions. Therefore, it is important to improve the knowledge on the regulation and function of individual OATPs, and to apply it for therapeutic considerations.
Lusková V., M. Svoboda, J. Koláfiová: The Effect of Diazinon on Blood Plasma Biochemistry in Carp (Cyprinus carpio L.). Acta Vet. Brno 2002, 71: 117-123.The aim of this study was to evaluate the effect of diazinon [0,0-diethyl-0-(2-isopropyl-6-methylpyrimidin-4yl) phosphorothioate] on common carp (Cyprinus carpio L.). The effect was assessed by comparing the biochemical blood plasma profiles of a control group and a group exposed to the effect of the pesticide Basudin 600 EW (containing 600 g.l -1 diazinon as the toxic substance). The activities of selected enzymes, metabolite concentrations and electrolytes were measured in 15 specimens of controls, K 1-2, and in 16 specimens, K 1-2 , exposed for 96 h to the effects of Basudin 600 EW at a concentration of 32.5 mg.l -1 . Compared with the control group, a significant decrease of cholinesterase (p < 0.01) and lactate dehydrogenase (p < 0.05) was ascertained in the experimental group. The values of alanine and aspartate aminotransferases, creatine kinase, alkaline and acide phosphatases were comparable in the experimental and control groups. The total protein and lactate concentration were significantly lower (p < 0.05) in the experimental group, compared with the control group. On the contrary, glucose concentration in the plasma of the experimental group was significantly higher (p < 0.01) than in that of the control group. The experimental group showed a significantly higher (p < 0.05) concentration of plasmatic natrium and potassium, and a significantly lower (p < 0.05) concentration of plasmatic calcium and phosphorus, compared with those in the control group. The above results of examinations of the biochemical blood plasma profile indicate a marked neurotoxic effect of diazinon in fishes.
The goal was to assess an effect of diazinon [0,0-diethyl 0-(2-isopropyl-6-methylpyrimidin-4yl) phosphorothioate] on common carp (Cyprinus carpio L.). The effect was assessed based on results of acute toxicity tests and on a comparison of results of haematological examination of a control and an experimental group exposed to Basudin 600 EW pesticide preparation (active substance 600 g.l -1 of diazinon). The acute toxicity test lasting 96 h was performed semistatically on common carp juveniles. Examination of erythrocyte and leukocyte profile was performed on 15 control and 25 experimental specimens of one-to-two-year-old common carp after 96 h of exposure to Basudin 600 EW in concentration of 32.5 mg . l -1 . The 96hLC50 value of Basudin 600 EW for common carp juveniles was 26.7 mg . l -1 . The experimental group of one-to two-year-old common carp showed significantly lower values (p < 0.01) of erythrocyte count (RBC), haemoglobin content (Hb) and haematocrit (PCV) compared to the control group. Values of MCV, MCH and MCHC were comparable in both groups during the study. In contrary, there was a significant decrease in leukocyte count (Leuko) (p < 0.01), as well as in both the relative and absolute lymphocyte count (p < 0.01) and a significant increase in both the relative and absolute count of developmental forms of neutrophile granulocytes: myelocytes (p < 0.01) and metamyelocytes (p < 0.05) in the experimental group. Relative and absolute count of monocytes and both the band-and segmented neutrophile granulocytes was comparable in both groups during the study. The diazinon-based Basudin 600 EW pesticide preparation was classified among harmful substances for fish. Changes in values of both the erythrocyte and leukocyte profile after exposure to diazinon-based preparation may be refered to disruption of haematopoiesis as well as to a decrease on non-specific immunity of the fish.Organophosphorous pesticide, acute toxicity, erythrocyte profile, leukocyte profile
Remarkably limited information is available about biological mechanisms that determine the disease entity of metastatic colorectal cancer in the liver (CRCLM) with no good clinical parameters to estimate prognosis. For the last few years, understanding the relationship between tumor characteristics and local immune response has gained increasing attention. Given the multifaceted roles of B-cell-driven responses, we aimed to elucidate the immunological imprint of B lymphocytes at the metastatic site, the interrelation with macrophages, and their prognostic relevance. Here we present novel algorithm allowing to assess a link between the local patient-specific immunological capacity and clinical outcome. The microscopy-based imaging platform was used for automated scanning of large-scale tissue sections and subsequent qualitative and quantitative analyses of immune cell subtypes using lineage markers and single-cell recognition strategy. Results indicate massive infiltration of CD45-positive leukocytes confined to the metastatic border. We report for the first time the accumulation of CD20-positive B lymphocytes at the tumor – liver interface comprising the major population within the large CD45-positive aggregates. Strikingly, functionally active, activation-induced cytidine deaminase (AID)-positive ectopic lymphoid structures were found to be assembled within the metastatic margin. Furthermore, the CD20-based data set revealed a strong prognostic power: patients with high CD20 content and/or ectopic follicles had significantly lower risk for disease recurrence as revealed by univariate analysis (p<0.001 for both) and in models adjusted for clinicopathological variables (p<0.001 and p = 0.01, respectively), and showed prolonged overall survival. In contrast, CD68 staining-derived data set did not show an association with clinical outcome. Taken together, we nominate the magnitude of B lymphocytes, including those organized in ectopic follicles, as novel prognostic marker which is superior to clinicopathological parameters. Findings emphasize anti-tumoral role of B cell-driven mechanism(s) and thus indicate a new way of thinking about potential treatment strategies for CRCLM patients.
Our results revealed OATP1B1 and OATP1B3 as high-affinity paclitaxel transporters expressed in ovarian cancer cell lines and tumor tissues, suggesting a role for these polypeptides in the disposition of paclitaxel during therapy. Conclusions:Our results revealed OATP1B1 and OATP1B3 as high-affinity paclitaxel transporters expressed in ovarian cancer cell lines and tumor tissues, suggesting a role for these polypeptides in the disposition of paclitaxel during therapy.
Organic anion transporting polypeptides (OATP, SLCO genes) mediate the uptake of endobiotics and drugs. Thus, their expression levels and pattern could be of relevance for cancer therapy. This prompted us to investigate the expression of poorly characterized OATPs, namely OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in hepatic cancer of different origin. First, mRNA levels of all eleven OATPs were determined in paired (cancerous and adjacent non-cancerous) specimens from 43 patients with primary liver cancer (hepatocellular carcinoma, HCC; cholangiocellular carcinoma, CCC) and liver metastases from colon tumors (MLT). Real-time RT-PCR analysis revealed that all OATPs, except OATP1C1 and OATP6A1, are extensively expressed in nearly all samples. In contrast to downregulated OATP1B1, OATP1B3, OATP1A2 and OATP2B1 in cancerous vs. non-cancerous samples, an increase in OATP2A1, OATP3A1, OATP4A1 and OATP5A1 mRNA levels was seen in tumors (up to 40-fold for OATP5A1 in the MLT group). Therefore, OATP2A1, OATP3A1, OATP4A1 and OATP5A1 were further investigated by immunofluorescence microscopy on paraffin-embedded cancerous and non-cancerous sections (seven per group). OATP-derived immunoreactivity was observed in plasma membranes and cytosol of hepatic tumor cells, and additionally, in various cytokeratin 19 positive bile ducts. An increased percentage of immunoreactive cells and a higher staining intensity in cancerous vs. non-cancerous paraffin sections paralleled higher mRNA levels of OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in cancerous tissues of HCC, CCC and MLT patients. The extensive expression of OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in hepatic tumors of different origin suggests that these transporters might be further exploited for the discovery of novel anticancer agents.
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