Publications by authors named "H Lage"

202 Publications

Energy metabolism of pregnant zebu and crossbred zebu dairy cattle.

PLoS One 2021 4;16(2):e0246208. Epub 2021 Feb 4.

Veterinary School, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

The purpose of this study was to determine the energy partition of pregnant F1 Holstein x Gyr with average initial body weight (BW) of 515.6 kg and Gyr cows with average initial BW of 435.1 kg at 180, 210 and 240 days of gestation, obtained using respirometry. Twelve animals in two groups (six per genetic group) received a restricted diet equivalent to 1.3 times the net energy for maintenance (NEm). The proportion of gross energy intake (GEI) lost as feces did not differ between the evaluated breeds and corresponded to 28.65% on average. The daily methane production (L/d) was greater for (P<0.05) F1 HxG compared to Gyr animals. However, when expressed as L/kg dry matter (DM) or as percentage of GEI there were no differences between the groups (P>0.05). The daily loss of energy as urine (mean of 1.42 Mcal/d) did not differ (P>0.05) between groups and ranged from 3.87 to 5.35% of the GEI. The metabolizable energy intake (MEI) of F1 HxG animals was greater (P < 0.05) at all gestational stages compared to Gyr cows when expressed in Mcal/d. However, when expressed in kcal/kg of metabolic BW (BW0,75), the F1 HxG cows had MEI 11% greater (P<0.05) at 240 days of gestation and averaged 194.39 kcal/kg of BW0,75. Gyr cows showed no change in MEI over time (P>0.05), with a mean of 146.66 kcal/kg BW0. 75. The ME used by the conceptus was calculated by deducting the metabolizable energy for maintenance (MEm) from the MEI, which was obtained in a previous study using the same cows prior to becoming pregnant. The values of NEm obtained in the previous study with similar non-pregnant cows were 92.02 kcal/kg BW0.75 for F1 HxG, and 76.83 kcal/kg BW0.75 for Gyr (P = 0.06). The average ME for pregnancy (MEp) was 5.33 Mcal/d for F1 HxG and 4.46 Mcal/d for Gyr. The metabolizability ratio, averaging 0.60, was similar among the evaluated groups (P>0.05). The ME / Digestible Energy (DE) ratio differed between groups and periods evaluated (P<0.05) with a mean of 0.84. The heat increment (HI) accounted for 22.74% and 24.38% of the GEI for F1 HxG and Gyr cows, respectively. The proportion of GEI used in the basal metabolism by pregnant cows in this study represented 29.69%. However, there were no differences between the breeds and the evaluation periods and corresponded to 29.69%. The mean NE for pregnancy (NEp) was 2.76 Mcal/d and did not differ between groups and gestational stages (P>0.05).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246208PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861432PMC
February 2021

Epoxylathyrane Derivatives as MDR-Selective Compounds for Disabling Multidrug Resistance in Cancer.

Front Pharmacol 2020 8;11:599. Epub 2020 May 8.

Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Lisbon, Portugal.

Background: Multidrug resistance (MDR) has been regarded as one of the major hurdles for the successful outcome of cancer chemotherapy. The collateral sensitivity (CS) effect is one the most auspicious anti-MDR strategies. Epoxylathyrane derivatives were obtained by derivatization of the macrocyclic diterpene epoxyboetirane A (), a lathyrane-type macrocyclic diterpene isolated from . Some of these compounds were found to strongly modulate P-glycoprotein (P-gp/ABCB1) efflux.

Purpose: The main goal was to develop lathyrane-type macrocyclic diterpenes with improved MDR-modifying activity, by targeting more than one anti-MDR mechanism.

Study Design/methods: In this study, the potential CS effect of compounds - was evaluated against gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29) human cancer cells and their drug-resistant counterparts, respectively selected against mitoxantrone (EPG85-257RNOV; EPP85-181RNOV; HT-RNOV) or daunorubicin (EPG85-257RDB; EPP85-181RDB; HT-RDB). The most promising compounds (, , and ) were investigated as apoptosis inducers, using the assays annexin V/PI and active caspase-3.

Results: The compounds were more effective against the resistant gastric cell lines, being the CS effect more significant in EPG85-257RDB cells. Taking together the IC values and the CS effect, compounds , , and exhibited the best results. Epoxyboetirane P (), with the strongest MDR-selective antiproliferative activity against gastric carcinoma EPG85-257RDB cells (IC of 0.72 µM), being 10-fold more active against this resistant subline than in sensitive gastric carcinoma cells. The CS effect elicited by compounds and appeared to be by inducing apoptosis caspase-3 activation. Structure-activity relationships of the compounds were additionally obtained through regression models to clarify the structural determinants associated to the CS effect.

Conclusions: This study reinforces the importance of lathyrane-type diterpenes as lead molecules for the research of MDR-modifying agents.
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http://dx.doi.org/10.3389/fphar.2020.00599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226783PMC
May 2020

Energy partitioning in cattle fed diets based on tropical forage with the inclusion of antibiotic additives.

PLoS One 2019 22;14(4):e0211565. Epub 2019 Apr 22.

Department of Animal Sciences, Veterinary School, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil, Pampulha.

The aim of this study was to describe energy partitioning in dairy crossbreed bulls fed tropical forage-based diets supplemented with different additives. Twenty F1 crossbred bulls (Holstein x Gyr) with initial and final live weight (LW) averages of 190 ± 17 and 275 ± 20 kg were fed sorghum (Sorghum bicolour) and Tanzania grass (Panicum maximum cv. Tanzania) silage (70:30 DM basis) with supplemented concentrate at a forage to concentrate ratio of 50:50. The bulls were allocated to four treatment: control groups (without additives), monensin [22 mg/kg monensin dry matter (DM)] (M), virginiamycin (30 mg/kg virginiamycin DM) (V), and combination (22 mg/kg DM of monensin and 30 mg/kg DM of virginiamycin) (MV), in a completely randomised design. The intake of gross energy (GE, MJ/d), digestible energy (DE, MJ/d), metabolizable energy (ME, MJ/d), as well as energy losses in the form of faeces, urine, methane, heat production (HE), and retained energy (RE) were measured. Faecal output was measured in apparent digestibility trial. Right after the apparent digestibility trial, urine samples were collected in order to estimate the daily urinary production of the animals. Heat and methane production were measured in an open circuit respirometry chamber. The intake of GE, DE, and ME of the animals receiving monensin and virginiamycin alone or in combination (MV) showed no differences (P>0.05) from the control treatment. However, the MV treatment reduced (P<0.05) the methane production (5.44 MJ/d) compared to the control group (7.33 MJ/d), expressed in MJ per day, but not when expressed related to gross energy intake (GEI) (CH4, % GEI) (P = 0.34). Virginiamycin and monensin alone or in combination did not change (P>0.05) the utilization efficiency of ME for weight gain, RE and net gain energy. This study showed that for cattle fed tropical forages, the combination of virginiamycin and monensin as feed additives affected their energy metabolism by a reduction in the energy lost as methane.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211565PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476472PMC
December 2019

Bacteria-mediated delivery of RNAi effector molecules against viral HPV16-E7 eradicates oral squamous carcinoma cells (OSCC) via apoptosis.

Cancer Gene Ther 2019 05 15;26(5-6):166-173. Epub 2018 Nov 15.

Charité Universitätsmedizin Berlin, Institute of Pathology, Charitéplatz 1, 10117, Berlin, Germany.

Delivery of RNAi-mediating shRNA molecules for gene silencing via bacteria, i.e. by transkingdom RNAi (tkRNAi) technology, is suggested to be a powerful alternative technique. In this work, the efficiency of bacterial delivery of shRNAs directed against HPV16-E7-specific mRNA to oral squamous carcinoma cells (OSCCs) was evaluated. E. coli were transfected with a plasmid encoding the inv locus and the Hlya gene to enable the bacteria to enter carcinoma cells and to escape from endocytotic vesicles. The bacterial penetration to the target cells was confirmed by DAPI staining. The HPV16-E7 mRNA expression in bacteria-treated OSCCs dropped to 61% of the controls as measured by qRT-PCR. Corresponding inhibition of the HPV16-E7 protein was confirmed by western blotting. The IC of bacteria-treated OSCCs was reduced to more than 75%. Flow cytometry assays showed higher total apoptosis and caspase-3 activation (6.6-fold and 8.4-fold respectively) in OSCCs following exposure to anti-HPV-E7  bacteria compared to anti-GFP bacteria (2-fold and 2.9-fold, respectively). In conclusion, it was demonstrated for the first time that tkRNAi technology is also useful for treatment of squamous carcinoma cells. Anti-HPV16-E7 shRNA-encoding bacteria can efficiently deliver RNAi effectors to OSCCs mediating a strong and specific gene silencing associated with triggering cell death.
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http://dx.doi.org/10.1038/s41417-018-0054-xDOI Listing
May 2019

Energy metabolism and partition of lactating Zebu and crossbred Zebu cows in different planes of nutrition.

PLoS One 2018 17;13(8):e0202088. Epub 2018 Aug 17.

Federal University of Minas Gerais, Veterinary School, Belo Horizonte, Minas Gerais, Brazil.

The aim of this study was to determine the energy metabolism and partition of lactating Gyr and F1 Holstein x Gyr (F1 HxG) cows in different planes of nutrition. Six F1 HxG and six Gyr cows with 130 days in milking (DIM) fed corn silage and concentrate were evaluated. The experiment consisted of four periods with different levels of feeding: 1st ad libitum dry matter intake (DMI) and the others with 5, 10 and 20% restricted DMI, related to the first one. An apparent digestibility assay was performed before measurements in the respiration chamber. Total feces were collected for three days. The cows were confined for 24h in the chamber in each period to determine methane and heat production (HP). F1 HxG had higher gross energy intake (GEI), metabolisable energy intake (MEI) and digestible energy intake (DEI). GE lost in feces was higher in F1 HxG (23.7% GEI) than in Gyr (20.5%) cows. Energy lost as methane and urine was similar between the groups. The metabolisability (q) was 0.67, and the efficiency of converting ME to NE (k) was 0.56. There was no difference in the energy requirements for maintenance between breeds (426.6 MJ/kg BW0,75 average value). The energy requirements for lactation were higher in F1 HxG animals due to the higher volume of milk produced, since there was no difference in energy requirements for production of one kg of milk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202088PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097685PMC
February 2019

Triterpenoids from Momordica balsamina with a Collateral Sensitivity Effect for Tackling Multidrug Resistance in Cancer Cells.

Planta Med 2018 Dec 11;84(18):1372-1379. Epub 2018 Jul 11.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.

The collateral sensitivity effect is among the most promising strategies for overcoming multidrug resistance in cancer. In this work, 28 cucurbitane-type triterpenoids (1: -28: ), previously isolated from the African medicinal plant and its derivatives, were evaluated for their collateral sensitivity effect on three different human cancer entities, gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29), each with two different multidrug-resistant variants. One was selected for its resistance to daunorubicin (EPG85-257RDB, EPP85-181RDB, HT-29RDB) and the other was selected for its resistance to mitoxantrone (EPG85-257RNOV, EPP85-181RNOV, HT-29RNOV). On gastric cell lines, the best results were obtained for compounds 3: and 10: , which exhibited a collateral sensitivity effect together with high antiproliferative activity. In turn, on colon cancer cell lines, the best multidrug resistance-selective antiproliferative effects were observed for derivatives 11, 13: , and 15: , which showed collateral sensitivity effects against both resistant variants. Compounds 11: and 3: were also the most selective against the multidrug resistance pancreatic cells lines. Some compounds, such 6, 10, 11: and 15: , were previously found to be strong P-glycoprotein modulators, thus highlighting their potential as promising leads for overcoming multidrug resistance in cancer cells.
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http://dx.doi.org/10.1055/a-0651-8141DOI Listing
December 2018

Exploring Jolkinol D Derivatives To Overcome Multidrug Resistance in Cancer.

J Nat Prod 2017 05 19;80(5):1411-1420. Epub 2017 Apr 19.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa , Avenue Prof. Gama Pinto, 1649-003 Lisbon, Portugal.

Macrocyclic monoacyl lathyrane derivatives bearing a benzoyl moiety were previously found to be strong ABCB1 modulators. To explore the effects of different substituents of the aromatic moiety, 14 new compounds (1.1-1.7, 1.10, and 2.1-2.4) were prepared from jolkinol D (1), obtained from Euphorbia piscatoria, and from jolkinodiol (2), its hydrolysis derivative. Compounds 1.8 and 1.9, having aliphatic moieties, were also obtained. The reversal of ABCB1-mediated MDR was evaluated through functional and chemosensitivity assays on the human ABCB1-gene-transfected L5178Y mouse T-lymphoma cell line. Structure-activity relationships showed that addition of electron-donating groups to the aromatic moiety improved the activity. The effects on the ATPase activity of the strongest modulator (1.3) and the inactive jolkinol D (1) were also investigated and compared. Moreover, in the chemosensitivity assay, most of the compounds interacted synergistically with doxorubicin. Compounds 1.1-1.10 and 2.1-2.4 were further assessed for their collateral sensitivity effect against the human cancer cells: EPG85-257 (gastric) and EPP85-181 (pancreatic), and the matching drug-selected cells EPG85-257RDB, EPG85-257RNOV, EPP85-181RDB, and EPP85-181RNOV. The most promising ones (1.8 and 1.10) along with compound 3, previously selected, were investigated as apoptosis inducers. The compounds were able to induce apoptosis through caspase-3 activation, with significant differences being observed between the parental and resistant cells.
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http://dx.doi.org/10.1021/acs.jnatprod.6b01084DOI Listing
May 2017

Gene Therapeutic Approaches to Overcome ABCB1-Mediated Drug Resistance.

Authors:
Hermann Lage

Recent Results Cancer Res 2016;209:87-94

Fachbereich Pathologie, Vivantes Klinikum Neukölln, Rudower Allee 48, 12351, Berlin, Germany.

Multidrug resistance (MDR) to pharmaceutical active agents is a common clinical problem in patients suffering from cancer. MDR is often mediated by over expression of trans-membrane xenobiotic transport molecules belonging to the superfamily of ATP-binding cassette (ABC)-transporters. This protein family includes the classical MDR-associated transporter ABCB1 (MDR1/P-gp). Inhibition of ABC-transporters by low molecular weight compounds in cancer patients has been extensively investigated in clinical trials, but the results have been disappointing. Thus, in the last decades alternative experimental therapeutic strategies for overcoming MDR were under extensive investigation. These include gene therapeutic approaches applying antisense-, ribozyme-, RNA interference-, and CRISPR/Cas9-based techniques. Various delivery strategies were used to reverse MDR in different tumor models in vitro and in vivo. Results and conclusions of these gene therapeutic studies will be discussed.
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http://dx.doi.org/10.1007/978-3-319-42934-2_6DOI Listing
June 2017

Jatrophane diterpenes and cancer multidrug resistance - ABCB1 efflux modulation and selective cell death induction.

Phytomedicine 2016 Aug 24;23(9):968-78. Epub 2016 May 24.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Avenue Prof. Gama Pinto, 1649-003 Lisbon, Portugal. Electronic address:

Background: Modulation of P-glycoprotein (ABCB1) and evaluation of the collateral sensitivity effect are among the most promising approaches to overcome multidrug resistance (MDR) in cancer. In a previous study, two rare 12,17-cyclojatrophanes (1-2) and other novel jatrophanes (3-4), isolated from Euphorbia welwitschii, were screened for collateral sensitivity effect. Herein, the isolation of another jatrophane (5) is presented, being the broader goal of this work to investigate the role of euphowelwitschines A (1) and B (2), welwitschene (3), epoxywelwitschene (4) and esulatin M (5) as ABCB1 modulators and/or collateral sensitivity agents.

Methods: Compounds 1-5 were evaluated for ABCB1 modulation ability through combination of transport and chemosensitivity assays, using a mouse T-lymphoma MDR1-transfected cell model. Moreover, the nature of interaction of compound 4 with ABCB1 was studied, using an ATPase assay. The MDR-selective antiproliferative activity of compound 5 was evaluated against gastric (EPG85-257) and pancreatic (EPP85-181) human cancer cells and their drug-selected counterparts (EPG85-257RDB, EPG85-257RNOV, EPP85-181RDB, EPP85-181RNOV). The drug induced cell death was investigated for compounds 4 and 5, using the annexin V/PI staining and the active caspase-3 assay.

Results: The jatrophanes 1-5 were able to modulate the efflux activity of ABCB1, and at 2µM, 3-5 maintained the strong modulator profile. Structure activity results indicated that high conformational flexibility of the twelve-membered ring of compounds 3-5 favored ABCB1 modulation, in contrast to the tetracyclic scaffold of compounds 1 and 2. The effects of epoxywelwitschene (4) on the ATPase activity of ABCB1 showed it to interact with the transporter and to be able to reduce the transport of a second subtrate. Drug combination experiments also corroborated the anti-MDR potential of these diterpenes due to their synergistic interaction with doxorubicin (combination index <0.7). Esulatin M (5) showed a strong MDR-selective antiproliferative activity against EPG85-257RDB and EPP85-181RDB cells, with IC50 of 1.8 and 4.8 µM, respectively. Compounds 4 and 5 induced apoptosis via caspase-3 activation. A significant discrimination was observed between the resistant cell lines and parental cells.

Conclusions: This study strengthens the role of jatrophane diterpenes as lead candidates for the development of MDR reversal agents, higlighting the action of compounds 4 and 5.
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http://dx.doi.org/10.1016/j.phymed.2016.05.007DOI Listing
August 2016

Crocin suppresses multidrug resistance in MRP overexpressing ovarian cancer cell line.

Daru 2016 Jun 24;24(1):17. Epub 2016 Jun 24.

Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, P. O. Box 91775-1365, Mashhad, Iran.

Background: Crocin, one of the main constituents of saffron extract, has numerous biological effects such as anti-cancer effects. Multidrug resistance-associated proteins 1 and 2 (MRP1 and MRP2) are important elements in the failure of cancer chemotherapy. In this study we aimed to evaluate the effects of crocin on MRP1 and MRP2 expression and function in human ovarian cancer cell line A2780 and its cisplatin-resistant derivative A2780/RCIS cells.

Methods: The cytotoxicity of crocin was assessed by the MTT assay. The effects of crocin on the MRP1 and MRP2 mRNA expression and function were assessed by real-time RT-PCR and MTT assays, respectively.

Results: Our study indicated that crocin reduced cell proliferation in a dose-dependent manner in which the reduction in proliferation rate was more noticeable in the A2780 cell line compared to A2780/RCIS. Crocin reduced MRP1 and MRP2 gene expression at the mRNA level in A2780/RCIS cells. It increased doxorubicin cytotoxicity on the resistant A2780/RCIS cells in comparison with the drug-sensitive A2780 cells.

Conclusion: Totally, these results indicated that crocin could suppress drug resistance via down regulation of MRP transporters in the human ovarian cancer resistant cell line.
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http://dx.doi.org/10.1186/s40199-016-0155-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920992PMC
June 2016

12,17-Cyclojatrophane and Jatrophane Constituents of Euphorbia welwitschii.

J Nat Prod 2015 Nov 12;78(11):2684-90. Epub 2015 Nov 12.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa , Avenue Prof. Gama Pinto, 1649-003 Lisbon, Portugal.

Euphowelwitschines A (1) and B (2), isolated from a methanolic extract of Euphorbia welwitschii, exhibit a rare combination of structural features in having a 5/8/8 fused-ring system and a 12,15-ether bridge. Moreover, the isolation of the additional new compounds welwitschene (3) and epoxywelwitschene (4) has provided insights into the biogenetic pathway of 12,17-cyclojatrophanes. The structures of 1-4 were determined by spectroscopic methods inclusive of 1D and 2D NMR experiments and X-ray crystallography for compounds 1 and 2. Preliminary information on the selective antiproliferative activity of compounds 1-4 is also described.
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http://dx.doi.org/10.1021/acs.jnatprod.5b00631DOI Listing
November 2015

Expression of Estrogen Receptors in OSCC in Relation to Histopathological Grade.

Anticancer Res 2015 Nov;35(11):5867-72

Department of Oral and Maxillofacial Surgery/Clinical Navigation, Campus Virchow-Clinic, Charité University Hospital, Berlin, Germany.

Background/aim: Estrogen receptor (ER)-mediated pathways are involved in the pathogenesis of several tumors. Preliminary studies have demonstrated a significant effect of ER agonists and antagonists on oral squamous cell carcinoma (OSCC) cell lines. Recent results suggest that ER subtype-specific expression patterns might depend on the grade of differentiation of OSCC. Therefore, the aim of the present study was to evaluate the expression of ERα and ERβ in OSCC and its correlation to histological tumor grade and gender.

Materials And Methods: Tumor sections of 25 patients (13 males and 12 females) retrieved from OSCC databases with two different histological gradings (well-differentiated, poorly differentiated) were evaluated. The detection of ERα and ERβ expression in tumor cells and corresponding healthy mucosa adjacent to tumor was performed using immunohistochemistry.

Results: Well-differentiated OSCC showed no significant difference between the expression of ERβ in tumor cells and corresponding mucosa. In poorly-differentiated OSCC the expression of ERβ was significantly higher in tumor cells than in corresponding mucosa. In patients without regular alcohol and/or nicotine abuse, there was no significant difference of ERβ expression in OSCC compared to corresponding healthy mucosa in contrast to patients having these risk factors. Expression of ERα was found in one tumor.

Conclusion: ERβ is the predominant ER sub-type expressed significantly higher in poorly-differentiated OSCC tumors compared to healthy mucosa adjacent to the tumor. Different expression patterns in relation to histological grade might suggest an influential role of ERβ in tumor (de-) differentiation of OSCC.
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November 2015

Discovery of substituted 1,4-dihydroquinolines as novel class of ABCB1 modulators.

Bioorg Med Chem 2015 Aug 15;23(15):5015-5021. Epub 2015 May 15.

Institute of Pharmacy, Martin Luther University, 06120 Halle, Germany. Electronic address:

Transmembrane efflux pumps are one main cause for multidrug resistance (mdr) of cancer. One hopeful approach to combate the mdr has been the development of inhibitors of the efflux pump activity. A novel class of small-molecule inhibitors of the most important efflux pump ABCB1 (P-glycoprotein) has been discovered. Inhibitory activities are discussed in relation to substituent effects. Most active compounds have been evaluated in first bioanalytical studies to reverse the mdr of an anticancer drug. Cellular toxicity and ABCB1 substrate properties of the compounds were investigated. A cellular induction of relevant efflux pump protein expressions was not observed under inhibitor application, so that our compounds are perspective candidates for further preclinical studies.
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http://dx.doi.org/10.1016/j.bmc.2015.05.016DOI Listing
August 2015

Nanolipoparticles-mediated MDR1 siRNA delivery reduces doxorubicin resistance in breast cancer cells and silences MDR1 expression in xenograft model of human breast cancer.

Iran J Basic Med Sci 2015 Apr;18(4):385-92

Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran ; Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

Objectives: P-glycoprotein (P-gp) is an efflux protein, the overexpression of which has been associated with multidrug resistance in various cancers. Although siRNA delivery to reverse P-gp expression may be promising for sensitizing of tumor cells to cytotoxic drugs, the therapeutic use of siRNA requires effective carriers that can deliver siRNA intracellularly with minimal toxicity on target cells. We investigated a special class of PEGylated lipid-based nanoparticles (NP), named nanolipoparticles (NLPs), for siRNA-mediated P-gp downregulation.

Materials And Methods: NLPs were prepared based on low detergent dialysis method. After characterization, we evaluated the effect of NLPs on siRNA delivery, and P-gp downregulation compared to oligofectamine™ (OFA) in vitro and in vivo.

Results: Our results showed a significant decrease in P-gp expression and subsequent enhancement of chemosensitivity to doxorubicin in vitro. Although the effectiveness of NLPs for in vitro siRNA delivery compared to OFA was limited, the results of in vivo studies showed noticeable effectiveness of NLPs for systemic siRNA delivery. siRNA delivery using NLPs could downregulate MDR1 in tumor cells more than 80%, while OFA had a reverse effect on MDR1 expression in vivo.

Conclusion: The results indicated that the prepared NLPs could be suitable siRNA delivery systems for tumor therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439454PMC
April 2015

The photodynamic effect of far-red range phthalocyanines (AlPc and Pc green) supported by electropermeabilization in human gastric adenocarcinoma cells of sensitive and resistant type.

Biomed Pharmacother 2015 Feb 24;69:145-52. Epub 2014 Nov 24.

Institute of Pathology, Charité Universitätsmedizin, Berlin, Germany.

Introduction: Electroporation (EP) is commonly applied for effective drug transport thorough cell membranes based on the application of electromagnetic field. When applied with cytostatics, it is called electrochemotherapy (ECT) - a quite new method of cancer treatment. A high-voltage pulse causes the formation of temporary pores in the cell membrane which create an additional way for the intracellular drug transport. In the current work, EP was effectively merged with the already known photodynamic therapy (PDT) to selective photosensitizers' delivery to diseased tissue. The application of electroporation can reduce the dose of applied drug.

Research Objective: The aim of research was to evaluate the effectiveness of photodynamic reaction using two near infrared cyanines (AlPc and Pc green) combined with electroporation in two human gastric adenocarcinoma cell lines.

Materials And Methods: Two human cell lines - EPG85-257P (parental) and EPG85-257RDB (resistant to daunorubicin) - of gastric cancer were used. The effect of two photosensitizers (aluminum 1,8,15,22-tetrakis(-phenylthio)-29H,31H-phthalocyanine chloride and Phthalocyanine green) was investigated. The efficiency of EP parameters was assessed by propidium iodide uptake. The viability assay was applied to analyse EP, PDT and EP-PDT effect. Cyanine localization was determined by confocal microscopy. Immunocytochemical evaluation of manganese superoxide dismutase and glutathione S-transferase-pi was determined after applied therapies.

Results: PDT in combination with EP affected the viability of EPG85-257P and EPG85-257RDB cells negatively while both cyanine were used. The most evident changes were observed in the following concentrations: 15, 10 and 5μM. The optimal field strength for enhanced EP-PDT was 800 and 1200V/cm. AlPc distributed selectively in the lysosomes of parental cell line.

Conclusions: PDT, enhanced by EP, caused decreased viability when compared to the application of PDT alone. Both phthalocyanines found to be more effective after electroporation. Due to the low concentration of light-sensitive compounds and safety of electroporation itself, a treatment plan can be an alternative therapeutic modality against gastric adenocarcinomas.
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http://dx.doi.org/10.1016/j.biopha.2014.11.017DOI Listing
February 2015

Discovery of 9,10-Dihydroacridines as Novel Class of ABCB1 Inhibitors.

Med Chem 2015 ;11(4):329-35

Institute of Pharmacy, Martin- Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.

Nonplanar 9,10-dihydroacridines were synthesized as promising C2 symmetric molecular scaffolds as inhibitors of the transmembrane efflux pump ABCB1. Within the series structure-activity relationships are discussed revealing the importance of hydrogen bond acceptor functions. A selectivity of ABCB1 inhibition is demonstrated for selected candidates and a bioanalytical study proved nontoxicity as well as missing ABCB1 substrate properties. The results encourage to further develop the promising class of ABCB1 inhibitors.
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http://dx.doi.org/10.2174/1573406410666141111100720DOI Listing
February 2016

Diterpenes from Euphorbia piscatoria: synergistic interaction of Lathyranes with doxorubicin on resistant cancer cells.

Planta Med 2014 Dec 5;80(18):1739-45. Epub 2014 Nov 5.

Instituto de Investigação do Medicamento (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.

Four new diterpenes were isolated from the methanolic extract of Euphorbia piscatoria, two ent-abietanes (1, 2) and two lathyrane-type macrocyclic diterpenes (3, 4), along with three known diterpenes (5-7). Their structures were characterized by spectroscopic methods, mainly 1D and 2D NMR ((1)H, (13)C, DEPT, COSY, HMBC, HMQC, and NOESY) experiments. Compound 2, with an unusual structure, might be considered intermediate in the biosynthesis of ent-abietane α,β-unsaturated lactones, commonly found in Euphorbia species. Therefore, a possible biogenetic pathway is proposed. The MDR reversal potential of macrocyclic diterpenes 3-5 was evaluated through a drug combination assay, using the L5178Y mouse T lymphoma cell line transfected with the human MDR1 gene. Compounds 3-5 were able to enhance, synergistically, the antiproliferative activity of doxorubicin (combination indexes < 0.5). Moreover, compounds 1-6 were also assessed for their antiproliferative activity on human MDR cancer cell models, namely gastric, pancreatic, and colon. Weak antiproliferative activity was observed for compounds 1 (IC50 = 66.02 ± 7.10 µM) and 4 (IC50 = 39.51 ± 3.82 µM) on the MDR gastric cell line.
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http://dx.doi.org/10.1055/s-0034-1383244DOI Listing
December 2014

Delivery of siRNAs to cancer cells via bacteria.

Methods Mol Biol 2015 ;1218:117-29

Charité Campus Mitte, Institute of Pathology, Charitéplatz 1, Berlin, 10117, Germany.

RNA interference (RNAi) technology is a promising approach for efficient silencing of a particular gene for cancer gene therapy. However, the main obstacle for the development of RNAi-based therapeutic approaches is the delivery of the RNAi effector molecules to target cells. One promising strategy to surmount this challenge is the application of nonpathogenic bacteria as a delivery vector to target cells. In this chapter, the design of invasive Escherichia coli is described. The strain carries a plasmid encoding short hairpin RNAs (shRNAs), a protein (invasin) necessary for endocytotic absorption of the bacteria by target cells, and listeriolysin O required for the lysis of endocytotic vesicles within the target cells.
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http://dx.doi.org/10.1007/978-1-4939-1538-5_7DOI Listing
June 2015

A cisplatin-resistant head and neck cancer cell line with cytoplasmic p53(mut) exhibits ATP-binding cassette transporter upregulation and high glutathione levels.

J Cancer Res Clin Oncol 2014 Oct 10;140(10):1689-704. Epub 2014 Jun 10.

Department of Otolaryngology, Head and Neck Surgery, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35033, Marburg, Germany.

Purpose: Head and neck squamous cell carcinoma (HNSCC) cell lines with cytoplasmically sequestered mutant p53 (p53(mut_c)) are frequently more resistant to cisplatin (CDDP) than cells with mutant but nuclear p53 (p53(mut_n)). The aim of the study was to identify underlying mechanisms implicated in CDDP resistance of HNSCC cells carrying cytoplasmic p53(mut).

Methods: Microarray analysis, quantitative reverse transcription polymerase chain reaction, Western blot analysis and immunocytochemistry were used to identify and evaluate candidate genes involved in CDDP resistance of p53(mut_c) cells. RNAi knockdown or treatment with inhibitors together with flow cytometry-based methods was used for functional assessment of the identified candidate genes. Cellular metabolic activity was assessed with the XTT assay, and the redox capacity of cells was evaluated by measuring cellular glutathione (GSH) levels.

Results: Upregulation of ABCC2 and ABCG2 transporters was observed in CDDP-resistant p53(mut_c) HNSCC cells. Furthermore, p53(mut_c) cells exhibited a pronounced side population that could be suppressed by RNAi knockdown of ABCG2 as well as treatment with the ATP-binding-cassette transporter inhibitors imatinib, MK571 and tariquidar. Metabolic activity and cellular GSH levels were higher in CDDP-resistant p53(mut_c) cells, consistent with a higher capacity to fend off cytotoxic oxidative effects such as those caused by CDDP treatment. Finally, ABCC2/G2 inhibition of HNSCC cells with MK571 markedly enhanced CDDP sensitivity of HNSCC cells.

Conclusions: The observations in this study point to a major role of p53(mut_c) in conferring a stem cell like phenotype to HNSCC cells that is associated with ABCC2/G2 overexpression, high GSH and metabolic activity levels as well as CDDP resistance.
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http://dx.doi.org/10.1007/s00432-014-1727-yDOI Listing
October 2014

Macrocyclic diterpenes resensitizing multidrug resistant phenotypes.

Bioorg Med Chem 2014 Jul 13;22(14):3696-702. Epub 2014 May 13.

Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. Electronic address:

Herein, collateral sensitivity effect was exploited as a strategy to select effective compounds to overcome multidrug resistance in cancer. Thus, eleven macrocyclic diterpenes, namely jolkinol D (1), isolated from Euphorbia piscatoria, and its derivatives (2-11) were evaluated for their activity on three different Human cancer entities: gastric (EPG85-257), pancreatic (EPP85-181) and colon (HT-29) each with a variant selected for resistance to mitoxantrone (EPG85-257RN; EPP85-181RN; HT-29RN) and one to daunorubicin (EPG85-257RD; EPP85-181RD; HT-29RD). Jolkinol D (1) and most of its derivatives (2-11) exhibited significant collateral sensitivity effect towards the cell lines EPG85-257RN (associated with P-glycoprotein overexpression) and HT-29RD (altered topoisomerase II expression). The benzoyl derivative, jolkinoate L (8) demonstrated ability to target different cellular contexts with concomitant high antiproliferative activity. These compounds were previously assessed as P-glycoprotein modulators, at non-cytotoxic doses, on MDR1-mouse lymphoma cells. A regression analysis between the antiproliferative activity presented herein and the previously assessed P-glycoprotein modulatory effect showed a strong relation between the compounds that presented both high P-glycoprotein modulation and cytotoxicity.
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http://dx.doi.org/10.1016/j.bmc.2014.05.006DOI Listing
July 2014

Nuclear-cytoplasmic PARP-1 expression as an unfavorable prognostic marker in lymph node‑negative early breast cancer: 15-year follow-up.

Oncol Rep 2014 Apr 18;31(4):1777-87. Epub 2014 Feb 18.

Department of Oncology and Division of Surgical Oncology, Wroclaw Medical University, 50-556 Wroclaw, Poland.

PARP-1 plays an important role in DNA damage repair and maintaining genome integrity by repairing DNA single-strand breaks (SSBs) by base excision repair (BER). The aim of the present study was to examine the expression of PARP-1 in breast cancer (BC) patients and to assess the relationship between the subcellular localization of this protein and clinicopathological characteristics. The reactivity of PARP-1 was analyzed by immunohistochemistry in a homogeneous group of 83 stage II ductal BC patients with a 15-year follow-up. Immunostaining of PARP-1 was also evaluated in 4 human BC cell lines and resistance prediction profile for 11 anticancer agents was performed using 3 models of drug-resistant cell lines. Nuclear-cytoplasmic expression (NCE) was associated with shorter overall survival, which was not statistically significant during the 10-year follow-up but became statistically significant after 10 years of observation, during the 15-year follow-up (P=0.015). Analysis performed in subgroups of patients with (N+) and without (N-) nodal metastases showed that NCE was associated with poor clinical outcome in N- patients (P=0.017). Multivariate analysis confirmed a significant impact of NCE on unfavorable prognosis in N- early BC. The presence of PARP-1 NCE may be a new potential unfavorable prognostic factor in lymph node- negative early BC.
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http://dx.doi.org/10.3892/or.2014.3024DOI Listing
April 2014

In vitro analysis of the relationships between metallothionein expression and cisplatin sensitivity of non-small cellular lung cancer cells.

Anticancer Res 2013 Dec;33(12):5255-60

Department of Pathomorphology and Oncological Cytology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland.

Background: Cisplatin-based therapy is a pivotal type of chemotherapy for non-small cell lung cancer (NSCLC) and chemoresistance to cisplatin represents one of the most significant barriers to improving long-term clinical outcomes.

Materials And Methods: The present study aimed at examining metallothionein (MT) expression in six NSCLC cell lines as well as examining effects of exposure to cisplatin on MT expression in the most cisplatin-resistant (97/97) and the cisplatin-sensitive (DV90) cell lines.

Results: The most cisplatin-resistant NSCLC cell line [97/97; (IC50)=4.659 μM] exposed to the highest concentration of cisplatin (10 μM) exhibited decreased nuclear MT expression (MTn=6) compared to cells cultured in medium with a lower concentration of cisplatin (0, 1 and 5 μM) (MTn=12). A higher cytoplasmic metallothionein expression (MTc=6) was found in the 97/97 cell line exposed to the highest concentration of cisplatin (10 μM), compared to cells cultured in the medium with lower concentrations of cisplatin (0, 1 and 5 μM) (MTc=3). The most cisplatin-sensitive NSCLC cell line (DV90; IC50=0.184 μM) was characterized by a significant decrease of both nuclear and cytoplasmic MT expression with increasing cisplatin concentrations (5 vs. 10 μM).

Conclusion: Nuclear and cytoplasmic expression of MT has no significant impact on the development of cisplatichemoresistance in NSCLC cell lines. The present study suggests that cisplatin resistance in NSCLC is metallothionein-independent.
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December 2013

The cell cycle arrest and the anti-invasive effects of nitrogen-containing bisphosphonates are not mediated by DBF4 in breast cancer cells.

Biochimie 2014 Apr 26;99:71-6. Epub 2013 Nov 26.

Department of Pharmaceutical Biotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Iran; Institute of Pathology, Charité Campus Mitte, University Medicine Berlin, Berlin, Germany. Electronic address:

Recent work has shown that a DBF4 analog in yeast may be a target of nitrogen-containing bisphosphonates. DBF4 is an essential protein kinase required for DNA replication from primary eukaryotes to humans and appears to play a critical role in the S-phase checkpoint. It is also required for cell migration and cell surface adhesion. The effects of Pamidronate, risedronate, or zoledronate on cell viability and DBF4 expression were measured via MTT assays and western blotting. In addition, FACS cell cycle analyses and invasion assays were conducted in cells in the presence of nitrogen-containing bisphosphonates to identify any correlations between DBF4 expression and S-phase arrest or anti-invasive effects of the bisphosphonates. Zoledronate transiently down-regulated DBF4 expression in all three cell lines in the first 24 h of the experiment, but after 72 h, DBF4 expression returned to the control levels in all treated cells. Following treatment of the tumor cells with the bisphosphonates, the number of cells in S-phase was increased. Pamidronate and zoledronate showed anti-invasive effects in BT20 cells. The anti-invasive effects of pamidronate, risedronate and zoledronate appeared after 48 h of exposure. In MDA-MB231 cells a reduction of invasiveness was only observed after 72 h of the pamidronate exposure. We finally concluded that the anti-invasive and cell cycle arrest-inducing effects of nitrogen-containing bisphosphonates are not DBF4 mediated, and other mediators are therefore needed to explain the observed complex behaviors.
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http://dx.doi.org/10.1016/j.biochi.2013.11.010DOI Listing
April 2014

YB-1 dependent oncolytic adenovirus efficiently inhibits tumor growth of glioma cancer stem like cells.

J Transl Med 2013 Sep 18;11:216. Epub 2013 Sep 18.

Institut für Experimentelle Onkologie & Therapieforschung, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str, 22, 81675 München, Germany.

Background: The brain cancer stem cell (CSC) model describes a small subset of glioma cells as being responsible for tumor initiation, conferring therapy resistance and tumor recurrence. In brain CSC, the PI3-K/AKT and the RAS/mitogen activated protein kinase (MAPK) pathways are found to be activated. In consequence, the human transcription factor YB-1, knowing to be responsible for the emergence of drug resistance and driving adenoviral replication, is phosphorylated and activated. With this knowledge, YB-1 was established in the past as a biomarker for disease progression and prognosis. This study determines the expression of YB-1 in glioblastoma (GBM) specimen in vivo and in brain CSC lines. In addition, the capacity of Ad-Delo3-RGD, an YB-1 dependent oncolytic adenovirus, to eradicate CSC was evaluated both in vitro and in vivo.

Methods: YB-1 expression was investigated by immunoblot and immuno-histochemistry. In vitro, viral replication as well as the capacity of Ad-Delo3-RGD to replicate in and, in consequence, to kill CSC was determined by real-time PCR and clonogenic dilution assays. In vivo, Ad-Delo3-RGD-mediated tumor growth inhibition was evaluated in an orthotopic mouse GBM model. Safety and specificity of Ad-Delo3-RGD were investigated in immortalized human astrocytes and by siRNA-mediated downregulation of YB-1.

Results: YB-1 is highly expressed in brain CSC lines and in GBM specimen. Efficient viral replication in and virus-mediated lysis of CSC was observed in vitro. Experiments addressing safety aspects of Ad-Delo3-RGD showed that (i) virus production in human astrocytes was significantly reduced compared to wild type adenovirus (Ad-WT) and (ii) knockdown of YB-1 significantly reduced virus replication. Mice harboring othotopic GBM developed from a temozolomide (TMZ)-resistant GBM derived CSC line which was intratumorally injected with Ad-Delo3-RGD survived significantly longer than mice receiving PBS-injections or TMZ treatment.

Conclusion: The results of this study supported YB-1 based virotherapy as an attractive therapeutic strategy for GBM treatment which will be exploited further in multimodal treatment concepts.
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http://dx.doi.org/10.1186/1479-5876-11-216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848904PMC
September 2013

[Resistance to medicinal tumor therapy. Current status].

Authors:
H Lage U Kellner

Pathologe 2013 Sep;34(5):398-402

Institut für Pathologie, Charité-Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, Berlin, Germany.

In the past multiple mechanisms could be identified that are involved in anticancer drug resistance; however, diagnostic assays for prediction of therapy response to classical cytostatic drugs did not enter routine clinical diagnostics. Only when new targeted drugs, e.g. tyrosine kinase inhibitors or therapeutic antibodies, were introduced in oncology were diagnostics for prediction of therapy response routinely preformed. First and foremost this was the result of the development of highly standardized techniques, i.e. exact mutation analysis in functional relevant codons of genes encoding signal proteins of cancer-related signal transduction pathways targeted by the new drugs. Due to increasing costs of health systems, in the future predictive diagnostics will probably become more and more important. Therefore, it will be necessary to develop improved diagnostic assays for prediction of individual therapy response.
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http://dx.doi.org/10.1007/s00292-013-1783-0DOI Listing
September 2013

Elevated nuclear S100P expression is associated with poor survival in early breast cancer patients.

Histol Histopathol 2013 04 31;28(4):513-24. Epub 2013 Jan 31.

Lower Silesian Centre of Oncology, Wrocław, Poland.

S100P - low molecular weight acidic protein has been shown to be involved in processes of proliferation, survival, angiogenesis, multidrug resistance and metastasis in various human malignancies. In breast cancer, S100P expression is associated with immortalization of neoplastic cells and aggressive tumour behaviour, indicating that this protein may have adverse prognostic value. We analyzed nuclear and cytoplasmic expression of S100P in 85 stage II breast cancer patients with a median follow up of 17 years. Immunohistochemical reactions were performed on paraffin sections of primary tumours, using monoclonal antibodies against S100P. We also studied prognostic value of S100P mRNA expression using the KM plotter which assessed the effect of 22,277 genes on survival in 2422 breast cancer patients. Moreover, the relationship was examined between expression of S100P in cells of four breast cancer cell lines and their sensitivity to the 11 most frequently applied cytotoxic drugs. Univariate and multivariate analyses showed that higher expression of nuclear S100P (S100Pn) was typical for cases of a shorter overall survival and disease-free time. KM plotter analysis showed that elevated S100P expression was specific for cases of a relapse-free survival and distant metastases-free survival. No relationship could be documented between expression of S100P and sensitivity of breast cancer cells to cytostatic drugs. We demonstrated that a high S100Pn expression level was associated with poor survival in early stage breast cancer patients. Since preliminary data indicated that expression of S100P was up-regulated by activation of glucocorticoid receptor and several agents manifested potential to activate or inhibit S100P promoter activity, this protein might become a therapy target and warrants further studies with respect to its prognostic, predictive and potentially therapeutic value.
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http://dx.doi.org/10.14670/HH-28.513DOI Listing
April 2013

Development of small-molecule P-gp inhibitors of the N-benzyl 1,4-dihydropyridine type: novel aspects in SAR and bioanalytical evaluation of multidrug resistance (MDR) reversal properties.

Bioorg Med Chem 2013 Jan 3;21(1):166-77. Epub 2012 Nov 3.

Institute of Pharmacy, Martin Luther University, 06120 Halle, Germany.

Novel series of N-benzyl 1,4-dihydropyridines have been prepared by facile syntheses. All relevant substituents of the molecular scaffold have been varied. The resulting compounds were biologically evaluated as P-glycoprotein (P-gp) inhibitors. Substitutions of the N-benzyl residue favour biological activity beside respective 3-ester functions. Most active compounds were further evaluated as multidrug resistance (MDR) modulators to restore the cytotoxic properties of varying daunorubicin applications.
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http://dx.doi.org/10.1016/j.bmc.2012.10.041DOI Listing
January 2013

Novel structurally varied N-alkyl 1,4-dihydropyridines as ABCB1 inhibitors: structure-activity relationships, biological activity and first bioanalytical evaluation.

Med Chem 2013 Jun;9(4):487-93

Institute of Pharmacy, Martin- Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.

Series of structurally varied N-alkyl 1,4-dihydropyridines and novel benzo-annelated derivatives as 1,4- dihydroquinolines have been characterized as ABCB1 inhibitors. Structure-activity relationships (SARs) are discussed. Cytotoxic activities of selected compounds have been determined. A first bioanalysis of ABCB1 substrate properties has been carried out in a cell-based model. Compounds with highest ABCB1 inhibiting activities were no substrates of ABCB1 and not transported by the efflux pump, thus profiling the new ABCB1 inhibitors.
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http://dx.doi.org/10.2174/1573406411309040002DOI Listing
June 2013

MRP2 (ABCC2, cMOAT) expression in nuclear envelope of primary fallopian tube cancer cells is a new unfavorable prognostic factor.

Arch Gynecol Obstet 2013 Mar 8;287(3):563-70. Epub 2012 Nov 8.

Department of Pathomorphology and Oncological Cytology, Wroclaw Medical University, ul. Borowska 213, 50-556 Wroclaw, Poland.

Objective: To determine the prognostic value of the immunohistochemical evaluation of the multidrug resistance-associated protein 2 (MRP2) expression, together with its subcellular localization in primary fallopian tube carcinomas (PFTCs).

Methods: The immunohistochemical analysis was performed using samples originating from 70 patients with PFTCs.

Results: (1) We documented that MRP2 can be localized in the plasma membrane (MRP2c), as well as in the nuclear envelope (MRP2n) of the PFTC cells. (2) Patients with more advanced stage, with progression of the disease and patients who died, showed significantly higher expression of the MRP2n. (3) Univariate and multivariate analyses showed that MRP2n is an unfavorable prognostic factor in PFTCs. (4) The analysis of the classic clinicopathological data revealed that only the FIGO stage had prognostic value, both in the univariate, as well as in multivariate analysis.

Conclusions: (1) This study suggests that MRP2n is a new disadvantageous prognostic factor in PFTCs and (2) that expression in nuclear envelope can be associated with lower differentiation of cancer cells and their resistance to the cisplatin. (3) We have also confirmed independent prognostic value of FIGO stage in PFTCs.
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http://dx.doi.org/10.1007/s00404-012-2589-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569580PMC
March 2013