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1
Juvale, Kapil [Verfasser]. "Development of New Breast Cancer Resistance Protein Inhibitors / Kapil Juvale." Bonn : Universitäts- und Landesbibliothek Bonn, 2013. http://d-nb.info/1044971266/34.
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Urfali, Cagri. "Reversal Of Breast Cancer Resistance Protein Mediated Multidrug Resistance In Mcf-7 Breast Adenocarcinoma Cell Line." Master's thesis, METU, 2012. http://etd.lib.metu.edu.tr/upload/12614062/index.pdf.
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Resistance to various chemotherapeutic agents is a major problem in success of
cancer chemotherapy. One of the primary reasons of development of multidrug
resistance (MDR) is the overexpression of ATP binding cassette (ABC) transporter
proteins. Breast cancer resistance protein (BCRP) belongs to ABC transporter family
and encoded by ABCG2 gene. BCRP is mainly expressed in MDR1 (P-glycoprotein)
lacking breast cancer cells. Overexpression of BCRP leads to efflux of
chemotherapeutic agents at higher rates, therefore, decreased levels of intracellular
drug accumulation. Despite the fact that several chemical modulators claim to restore
BCRP-mediated increased drug efflux, these modulators were shown to display
various side effects, precluding their clinical use. Therefore, to reverse BCRPmediated
MDR phenotype by a modulator with minimum cytotoxicity may increase
clinical benefits and minimize side effects.
3
Mumin, Dk Nuramalina Hafizah Pg Hj. "Acquired resistance to HSP90 inhibition in triple-negative breast cancer." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:d99dfe58-c147-4086-a82d-f10825c3cf87.
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Heat shock protein 90 (HSP90), a conserved molecular chaperone, has become a potential molecular target for cancer therapeutics. HSP90 inhibition (HSP90i) causes inhibition of several oncogenic pathways simultaneously and leads to anti-cancer activities in multiple cancers including in triple-negative breast cancer (TNBC). TNBC is a subtype of breast cancer with poor prognosis and lack of approved targeted therapies. Although HSP90i has shown promising initial clinical data, resistance to HSP90i can still arise in TNBC patients and its resistance mechanisms are not yet understood. In this study, using an in vitro system, we report for the first time the isolation of TNBC cells with acquired resistance to HSP90i. Proteome and whole transcriptome profiling, and a bioactive small molecule screen were performed to identify the molecular basis of resistance to HSP90i and potential therapeutic approaches to overcome acquired resistance to HSP90i in TNBC cells. Two independent HSP90i-resistant clones were acquired through prolonged exposure of a TNBC cell line (Hs578T) to HSP90i. The clones showed significant resistance to HSP90i, notably to resorcinol-based HSP90i. The HSP90i-resistant clones also shared genomic sequence variants, suggesting a pre-existing population of resistant cells within the parental cells. We demonstrate that upregulated expression of UGT1A9, possibly due to an increased intrinsic oxidative stress, is associated with acquired resistance to resorcinol-based HSP90i in TNBC cells, and sensitivity to HSP90i can be restored with a competitive inhibitor of UGT1A9. The HSP90i-resistant clones also exhibited slower growth and upregulated IL6- mediated JAK2-STAT3 survival signalling pathway, which might contribute to the crossresistance to chemotherapeutics and other targeted therapies seen in the clones. Finally, we demonstrate that inhibition of JAK2-STAT3 signalling pathway is able to increase the cytotoxic effects of HSP90i to TNBC cells. We conclude that by using in vitro assays, we are able to identify potential mechanisms of acquired resistance to HSP90i in TNBC cells. We propose that expression of UGT1A9 or STAT3 might be a potential biomarker of sensitivity to HSP90i in TNBC cells. A combined inhibition of HSP90 and JAK2 might be a potential therapeutic approach for the development of effective targeted therapies in TNBC patients.
4
Zhang, Yi. "Potential impact of breast cancer resistance protein on drug disposition during pregnancy /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/7970.
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Rainey, Jenna. "The Regulation of Multidrug Resistance Phosphoglycoprotein (MDR1/P-gp) and Breast Cancer Resistance Protein (BCRP) in the Human Placenta." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/19961.
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Multidrug resistance phosphoglycoprotein (MDR1/P-gp) and breast cancer resistance protein (BCRP) were first isolated in chemoresistant cancer cells and have since been found in a variety of normal tissue, including the placenta. The potential function of MDR1/P-gp and BCRP in the human placenta is to protect the fetus from maternally circulating endogenous steroids and hormones, therapeutic drugs and toxins. The objective of this study was to examine the role of maternal steroids in the regulation of MDR1/P-gp and BCRP in the human placenta. Trophoblast cells were isolated from term placenta tissues and immunohistochemistry, western blot analysis and transport studies were used to determine the effect of maternal steroids on MDR1/P-gp and BCRP regulation. Maternal steroids, present at high concentrations in maternal serum, did not have an effect on BCRP in human syncytiotrophoblast. Estrogen and progesterone did not alter MDR1/P-gp levels in human syncytiotrophoblast, but cortisol significantly decreased MDR1/P-gp levels.
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Pick, Anne-Kathrin [Verfasser]. "Funktionelle Untersuchungen des ABCTransporters Breast Cancer Resistance Protein (BCRP) / Anne-Katrin Pick. Mathematisch-Naturwissenschaftliche Fakultät." Bonn : Universitäts- und Landesbibliothek Bonn, 2011. http://d-nb.info/1017217661/34.
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Krapf, Michael [Verfasser]. "Investigation of Quinazoline Derivatives as Inhibitors of Breast Cancer Resistance Protein (BCRP/ABCG2) / Michael Krapf." Bonn : Universitäts- und Landesbibliothek Bonn, 2018. http://d-nb.info/1160594155/34.
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Yeboah, Dorothy. "Expression and regulation of Breast Cancer Resistance Protein in the human placenta and fetal membranes." Thesis, University of Ottawa (Canada), 2007. http://hdl.handle.net/10393/27942.
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Breast Cancer Resistance Protein, BCRP, is highly expressed in many different tumor tissues conferring multi-drug resistance against many chemotherapy drugs. BCRP has also been reported to be present in normal tissues including the human placenta during pregnancy. It is believed that in the placenta, BCRP controls the levels of toxins, drugs and xenobiotics that may cross maternal circulation into fetal circulation.
The expression of BCRP was examined in the human placenta and in placental membranes (amnion and chorion leave) and attached decidua. In addition, the effect of cytokines and hypoxia on BCRP expression in placental cells was examined in vitro.
BCRP was found to be highly expressed in the placenta throughout pregnancy as well as in the amnion, chorion laeve and attached decidua. Our data suggest that increased cytokine expression and reduced oxygen levels may not have any effect on BCRP mRNA or protein levels in the placental syncytiotrophoblast cells. This may suggest that BCRP is stably expressed in the placenta, even under adverse conditions, and may imply that activity of this transporter protein is essential for normal placental function.
9
KIM, Young-Hak. "Expression of breast cancer resistance protein is associated with a poor clinical outcome in patients with small-cell lung cancer." Kyoto University, 2011. http://hdl.handle.net/2433/135385.
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Cooray, H. C. "Breast cancer resistance protein (BCRP) at the blood-brain barrier and its interactions with steroidal compounds." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597979.
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Five different plant polyphenols (resveratrol, hesperetin, quercetin, daidzein and silymarin) were shown to interact with BCRP expressed in MCF7/MR and K562/BCRP cells, significantly increasing the accumulation of mitoxantrone and bodipy prazosin above control levels. They also stimulated the BCRP-associated ATPase activity in vesicles derived from Lactococcus lactis bacteria transformed with BCRP cDNA. None of these polyphenols had any effects on the long-term expression of BCRP in MCF7/MR cells. Inhaled corticosteroids have revolutionized the treatment of chronic obstructive pulmonary disease but cause long term suppression of the hypothalamic-pituitary-adrenal (HPA) axis, leading to low cortisol levels. It has been suggested that P-gp at the BBB may influence suppression of the HPA by oral corticosteroids. Five inhaled corticosteroids were tested for their ability to modulate P-gp and BCRP function. Beclomethasone dipropionate, mometasone furoate and the newer ciclesonide used at 5 and 10 μM increased the accumulation of mitoxantrone in BCRP-expressing MCF7/MR cells, and the accumulation of calcein in P-gp expressing SW620/R cells, though triamcinolone acetonide and budesonide had no inhibitory effects. Beclomethasone, mometasone and ciclesonide at 5 μM enhanced the cytotoxicity of doxorubicin in SW620/R cells. These three compounds as well as budesonide stimulated the BCRP-associated ATPase activity in L. lactis vesicles expressing BCRP. Both the plant polyphenols and the three corticosteroids examined in this study could either be ‘fast diffusing’ or competitive substrates of BCRP, inhibiting the efflux of another substrate while stimulating the BCRP-associated ATPase activity. These results establish that BCRP is present at the BBB and may modulate the access of both dietary and therapeutic steroidal compounds into the brain.
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Steggemann, Kerstin [Verfasser]. "Design und Synthese neuartiger Inhibitoren für den ABC-Transporter Breast Cancer Resistance Protein / Kerstin Steggemann. Mathematisch-Naturwissenschaftliche Fakultät." Bonn : Universitäts- und Landesbibliothek Bonn, 2011. http://d-nb.info/1016262256/34.
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Kaur, Manjit. "Phytochemical mediated modulation of breast cancer resistance protein at the blood brain barrier and blood cerebrospinal fluid barrier." Thesis, Aston University, 2016. http://publications.aston.ac.uk/30065/.
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Drug delivery to the central nervous system (CNS) is significantly hindered by thepresence of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier(BCSFB) and associated drug efflux transporter proteins. The aim of this work was to modulate the expression of breast cancer resistance protein (BCRP) at each barrier site using phytochemical modulators. In-vitro cellular models of both the BBB (PBMEC/C1-2) and BCSFB (Z310) were utilised and 18 phytochemical modulators screened for their cellular toxicity with IC50 values for the majority of phytochemicals being in excess of 100 μM. Intracellular accumulation of H33342 was assessed in each barrier cell line to determine short-term modulation of BCRP efflux or long-term modulation of protein expression. Incubations with modulators demonstrated significant inhibition of BCRP efflux activity for a range of modulators in both cell lines with TMF (1-100 μM) demonstrating a > 6 fold increase in intracellular accumulation. Similarly, many modulators demonstrated proposed protein-level modulation of BCRP resulting in increases or decreases in H33342 accumulation following a 24 hour exposure. Western blotting subsequently confirmed that quercetin and naringin for PBMEC/C1-2 and baiclain and flavone for Z310 induced BCRP expression (to 2-3 fold of control) whereas curcumin and 17-β-estradiol for PBMEC/C1-2 and silymarin, quercetin and 17-β-estradiol for Z310 down-regulated BCRP expression (to 0.24-0.4 fold of control). This was further confirmed in substrate transport studies using permeable insert models which demonstrated functional changes in the permeabilityof BCRP substrates across both barrier models. Subsequently the regulation of BCRP by AhR was confirmed through siRNAknockdown of AhR, which resulted in a significant decrease in BCRP geneexpression in both cell lines. Furthermore the induction/down-regulation effects on BCRP were, in general, diminished following AhR knockdown, suggesting AhR plays an important role in mediating the genomic/proteomic alterations in BCRP expression when exposed to phytochemicals.
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Le, Roux Heloise. "The effect of MKP-1 inhibition on the cytotoxicity of chemotherapeutic drugs in breast cancer." Thesis, Stellenbosch : Stellenbosch University, 2012. http://hdl.handle.net/10019.1/71779.
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Thesis (MSc)--Stellenbosch University, 2012.ENGLISH ABSTRACT: Introduction: Cancer is an emerging health problem in South Africa, with breast cancer being one of the leading cancers affecting women globally. Therefore, there is a need to find novel targets to improve the therapeutic options for these patients. A recently proposed target is the mitogen-activated protein kinase phosphatase-1 (MKP-1). Studies have suggested that mitogen-activated protein kinase phosphatases are involved in the development of cancer and play an important role in the response of cancer cells to chemotherapy. Additionally, numerous studies have indicated that there is increased expression of MKP-1 in breast cancers where its over-expression is proposed to be a significant mediator in chemo-resistance. We propose that inhibition of MKP-1 will increase the cytotoxic effect of doxorubicin in breast cancer cells, thus making the cells more responsive to treatment leading to increased cell death through autophagy and apoptosis. Methods: In MDA-MB231 cells, MKP-1 was inhibited using sanguinarine or MKP-1 siRNA and this was compared to a known inducer of MKP-1, dexamethasone. MDA-MB231 cells were treated with doxorubicin alone or in combination with MKP-1 inhibitors or an inducer. Following treatment, cell death was determined by trypan blue and a caspase glo assay as well as with western blotting. Autophagy was determined by western blotting and flow cytometry. LC3 and p62 were used as markers of autophagy and caspase 3 and PARP as apoptosis markers. Likewise, the level of MKP-1 expression under conditions of MKP-1 induction, inhibition or silencing was evaluated by means of western blotting. C57BL6 tumour bearing mice was used to analyse apoptosis and autophagy in vivo under conditions of MKP-1 inhibition, using sanguinarine, together with doxorubicin treatment. Western blotting was used to determine levels of caspase 3, LC3, p62 and MKP-1 expression. Results and discussion: A concentration and time curve indicated that 5 μM doxorubicin reduced cell viability in the MDA-MB231 cells significantly after 24 hours of treatment. MKP-1 expression was significantly reduced with sanguinarine and MKP-1 siRNA. Furthermore, our results indicate a significant increase in apoptosis in MDA-MB231 cells when treated with doxorubicin, under conditions of MKP-1 inhibition or MKP-1 silencing. Also, an increase in autophagic activity was observed following treatment with doxorubicin in combination with sanguinarine. Whole excised tumours of C57BL6 mice also showed an increase in apoptosis and autophagy following treatment with sanguinarine in combination with doxorubicin. This indicates that the inhibition of MKP-1 with sanguinarine sensitized the MDA-MB231 cells and E0771 cell tumours to doxorubicin-induced-apoptosis through a mechanism involving autophagy. Conclusion: This is an encouraging finding that could hopefully be used in future studies to overcome doxorubicin-resistance in breast cancer cells overexpressing MKP-1. Targeting MKP-1 can have potential therapeutic benefits for breast cancer patients by making chemotherapy more effective. Sanguinarine thus has potential to be developed as a clinically relevant inhibitor of MKP-1 which could provide a novel avenue for therapeutic intervention in combination with chemotherapy in breast cancer patients.
AFRIKAANSE OPSOMMING: Inleiding: Kanker is 'n vinnig groeiende gesondheidsprobleem in Suid-Afrika, met borskanker as een van die vernaamste kankers wat vroue wêreldwyd raak. Daar is dus 'n behoefte aan nuwe terapeutiese opsies vir hierdie pasiënte en mitogeen-geaktiveerde proteïenkinase fosfatase-1 (MKP-1) is onlangs voorgestel as ‘n moontlike teiken. Verskeie studies toon dat mitogeen-geaktiveerde proteïenkinase fosfatases betrokke is by die ontwikkeling van kanker en ook belangrike rolspelers is in die reaksie van kanker op chemoterapie. Daarbenewens toon talle studies dat daar verhoogde MKP-1 uitdrukking in borskanker is, asook dat dit ‘n belangrike bemiddelaar is vir die weerstand wat borskanker teen chemoterapie bied. Ons het dus voorgestel dat die inhibisie van MKP-1 die sitotoksiese effek van doxorubicin op borskanker selle sal verhoog; sodoende sal die kanker selle beter reageer op behandeling en dit sal dus lei tot verhoogde seldood deur autofagie en apoptose. Metodes: MKP-1 is geïnhibeer met behulp van sanguinarine of MKP-1 siRNA in MDA-MB231 selle en dit is vergelyk met 'n bekende MKP-1 induseerder, dexamethasone. MDA-MB231 selle is met doxorubicin alleen behandel of in kombinasie met MKP-1 inhibeerders of ‘n induseerder. Seldood is bepaal deur middel van ‘n trypan blou en kaspase toetsingsmetode, asook met die westelike kladtegniek. Autofagie is bepaal deur westelike kladtegniek en vloeisitometrie. LC3 en p62 is gebruik as merkers van autofagie en kaspase 3 en PARP is as apoptose merkers gebruik. MKP-1 uitdrukking is geëvalueer deur middel van westelike kladtegniek. C57BL6 muise met kankeragtige gewasse is gebruik om apoptose en autofagie in vivo te ondersoek. MKP-1 is geïnhibeer met sanguinarine en die muise is behandel met ‘n kombinasie van sanguinarine en doxorubicin. Kaspase 3, LC3, p62 en MKP-1 uitdrukking is bepaal deur middel van die westelike kladtegniek. Resultate en bespreking: ‘n Konsentrasie en tyd kurwe het aangedui dat 5 μM doxorubicin die MDA-MB231 selle se lewensvatbaarheid aansienlik verminder het na 24 uur. MKP-1 uitdrukking is ook aansienlik verminder met sanguinarine en MKP-1 siRNA. Verder dui die resultate op 'n beduidende toename in apoptose in MDA-MB231 selle na behandeling met doxorubicin onder toestande van MKP-1 inhibisie. 'n Toename in autofagiese aktiwiteit is waargeneem na behandeling met doxorubicin en sanguinarine. Die kankeragtige gewasse van die C57BL6 muise toon ook 'n toename in apoptose en autofagie na behandeling met sanguinarine en doxorubicin. Hierdie resultate dui daarop dat die inhibisie van MKP-1 met sanguinarine die MDA-MB231 selle en E0771 sel gewasse gesensitiseer het tot doxorubicin-geïnduseerde apoptose deur middel van ‘n meganisme wat autofagie insluit. Gevolgtrekking: Hierdie bevinding kan hopelik in toekomstige studies gebruik word om doxorubicin weerstand te oorkom in borskanker selle waar MKP-1 verhoog is. Deur MKP-1 te teiken, kan dit lei tot potensiële terapeutiese voordele vir borskanker pasiënte en sodoende kan dit chemoterapie meer effektief maak. Sanguinarine het dus die potensiaal om ontwikkel te word as ‘n klinies relevante inhibeerder van MKP-1 wat sodoende kan dien as terapeutiese intervensie in kombinasie met chemoterapie vir borskanker pasiënte.
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Vilatte, Sylvie. "Influence du neuropaludisme sur l'expression et la fonctionnalité des pompes d'efflux cérébrales : application au passage cerebral de la mefloquine." Paris 11, 2007. http://www.theses.fr/2007PA114828.
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Le neuropaludisme (NP) est la complication majeure du paludisme à Plasmodium falciparum chez l’homme. Ce travail a exploré l’influence du NP sur le passage cérébral de la méfloquine (MQ). Le passage cérebral d’un xénobiotique est lié aux protéines d’efflux présentes au niveau de la barrière hémato-encéphalique, la P-glycoprotéine (P-gp) et la Breast Cancer Resistance Protein (BCRP). Nous avons étudié le passage cérébral de MQ chez la souris saine et la souris impaludée et évalué l’influence des protéines d’efflux cérébrales sur ce passage. Nos travaux ont montré chez la souris saine que MQ était substrat de la P-gp et que son passage cérébral était stéréosélectif. Chez la souris impaludée, l’expression et la fonctionnalité de la P-gp et de la BCRP ne sont pas altérées mais le passage cérébral de MQ est diminué. Les modifications de pharmacocinétique cérébrale de MQ pourraient être dues à une variation du flux sanguin cérébral dans cette maladieCerebral malaria (CM) is the most severe complication of Plasmodium falciparum infection in humans. In this work, we studied the influence of CM on the cerebral uptake of mefloquine (MQ). Cerebral transport of drugs are restricted by efflux pumps in the blood-brain barrier as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). We studied the cerebral transport of MQ in healthy mice and infected mice and evaluated the role of the cerebral efflux pumps in this uptake. We showed that, in healthy mice, MQ is a P-gp substrate and that its cerebral uptake is stereoselective. In infected mice P-gp and BCRP activity is not altered by CM but the cerebral uptake of MQ is decreased. This modification of the cerebral pharmacokinetic of MQ could be due to the decrease of the cerebral blood flow reported by other authors in CM models
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Wang, Fen. "In silico and in vitro determination of substrate specificity for Breast Cancer Resistance Protein (BCRP) transporter at the blood-brain barrier." Thesis, Uppsala universitet, Institutionen för farmaci, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-444527.
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Background The Breast Cancer Resistance Protein (BCRP) drug transporter is important for drug disposition and plays a critical role in regulating drug entry into the brain. Its substrate spectrum overlaps with substrates of Multi Drug Resistance Protein 1 (MDR1, P-gp), which influences and complicates the interpretation of data on drug distribution into tissues (e.g. brain). Distinguishing BCRP mediated transport from the transport by the MDR1 is often problematic. However, with new in vitro tools, this is now possible. In this project, two drug compounds, i.e. Dantrolene and Ritonavir, were investigated using these new in vitro models. The results from the experimental in vitro assay were matched with molecular dynamics (MD) simulations. Using coarse-grained (CG) simulations, a model of the BCRP transporter in a lipid bilayer was built, this model is based on the human BCRP structure revealed by Taylor et al (2017). Simulations were run for Dantrolene (a known substrate of BCRP) independently three times, and another with Ritonavir (a non-substrate) three times. Aim To determine substrate specificity for the BCRP transporter for two compounds, and to construct a CG model of BCRP transporter to see whether in silico methods can be used as an alternative for assessing substrate specificity. Methods Madin-Darby canine kidney (MDCK) II cell line with no endogenous canine MDR1 (cMDR1) expression (MDCKcMDR1-KO), overexpressing human MDR1 (hMDR1) (MDCK-hMDR1cMDR1-KO) and stable expression of human BCRP (hBCRP) (MDCK-hBCRPcMDR1-KO) cells were cultured and used in Transwell experiments. Samples were analyzed using LC-MS/MS to determine the substrate concentrations. Apparent permeability and efflux ratio was calculated and evaluated. MD simulations used the Martini 3 CG force field, and were run with Gromacs (version 2020.4). Tools including MODELLER, INSANE and others were used to construct the initial model (Webster, 2000; Wassenaar et al., 2015), for parameterization of substrate and non-substrate molecules. And visual inspection was done with the visual molecular dynamics (VMD) program and PyMOL. Results In vitro transport experiment confirmed that Dantrolene is a BCRP specific substrate, and Ritonavir is MDR1 specific substrate. Following simulations of these two compounds, Dantrolene is observed to stay in the transmembrane domains (TMD) for a certain period (on average several hundreds of nanoseconds), while Ritonavir is not found to bind in the TMD, which provides a proof of concept for future studies.
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Tiwari, Aadhya [Verfasser]. "Role of Y-Box Binding Protein-1 mediated cell signaling in proliferation and radiotherapy resistance of breast cancer cells / Aadhya Tiwari." Tübingen : Universitätsbibliothek Tübingen, 2021. http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-937376.
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Pillay, Leeshan. "The integrated effects of selected inducers of endoplasmic reticulum stress, the unfolded protein response and apoptosis on P-Glycoprotein mediated drug resistance in MCF-7 breast carcinoma cells." University of the Western Cape, 2015. http://hdl.handle.net/11394/4459.
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>Magister Scientiae - MScPurpose: One of the leading causes of death reported in women worldwide is breast cancer. Manytumours, including breast cancer, associated with poor prognosis, have received a renewed focus and increased perspective with regard to drug discovery and innovation towards developing rational combination regimens of first-line anticancer drugs with novel compounds that target diverse hallmarks of the cancer phenotype. Multidrug resistance (MDR), which has been found to significantly decrease the efficacy of anticancer drugs and causes tumor recurrence, has been a major challenge in clinical cancer treatment with chemotherapeutic drugs for decades. Several mechanisms of overcoming drug resistance have been postulated and the well known P-glycoprotein (P-gp) including other drug efflux transporters are considered to be critical in pumping anticancer drugs out of cells which in turn results in unsuccessful chemotherapy treatments. The endoplasmic reticulum (ER) is an interconnecting organelle which synthesizes proteins and its quality control processes ensures the proper protein folding, post-translational modifications and conformation of secretory and trans-membrane proteins. Previous studies demonstrated that geldanamycin (GA), a benzoquinone ansamycin antibiotic, the antibiotic, tunicamycin (TM) and the sesquiterpene lactone, thapsigargin (TG) have been found to cause ER stress and consequently, cellular arrest. GA is known to manifest anti-cancer activity through the inhibition of Hsp90-chaperone, TM interferes with N-glycosylation of newly synthesized proteins triggering the unfolded protein response, while TG inhibits intracellular Ca2+ ATPases resulting in increased cytosolic Ca2+. Cellular stress conditions, lead to accumulation of unfolded or misfolded proteins in the endoplasmic reticulum lumen which results in a unfolded protein response (UPR) to maintain cell survival in cancer cells. ERS has been previously reported to enhance MDR1 transcriptional induction and P-gp transport function in cancer cells, however, prolonged endoplasmic reticulum stress conditions and inadequate unfolded protein response force cells undergo apoptosis. In this study, we examined the effects of GA, TG and TM alone and in combination to determine the cellular response of the MCF-7 breast carcinoma cell line with regard to proliferation and P-gp-mediated drug efflux activity and apoptosis. Methods: Analyses of MCF-7 breast carcinoma cells exposed to Endoplasmic Reticulum Stress (ERS) inducers geldanamycin, thapsigargin and tunicamycin, alone and in combination, included growth curves alone and in the presence of 24 hour IC50 inhibitory concentrations of the 3 ERS inducers alone, dose-response curves (MTT cytotoxicity assays) of the ERS alone and in combination, analysis of P-glycoprotein-mediated efflux pump activity in the presence of the ERS inducers alone and in combination (Calcein-AM efflux assays), analysis of viability, cytotoxicity and early apoptosis via caspase-3/7 expression (Triplex assay) and morphological staining of apoptotic and/or necrotic cells in the presence of IC50 inhibitory concentrations of the ERS inducers alone with Annexin V-FITC. Results: This study investigated the effects of Endoplasmic Reticulum Stress (ERS) inducers on growth and proliferation of MCF-7 breast carcinoma cells in culture. The MCF-7 cell line was exposed to different concentrations of ERS inducers alone and in combination with each other. All responses occurred in a dose- and time- dependent manner. When combined at equimolar log dose concentrations, integrated effects yielded enhanced cytotoxic properties as IC50 values were drastically decreased in combination as opposed to single ERS inducer responses. Combined effect on P-glycoprotein-mediated drug efflux activity yielded minor but insignificant decreases in efflux pump activity at different time intervals as opposed to the increase in cellular efflux in the presence of the ERS inducers alone at different time intervals. Caspase-3/7 apoptotic protein expression was increased as log doses of ERS inducers alone were increased, leading to cell necrosis at higher cytotoxic concentrations. The determined IC50 growth inhibitory concentrations after 24 hours were confirmed by the Annexin V-FITC demonstrating early apoptotic, necrotic and viable cells in the presence of the ERS inducers alone. Conclusion: This study demonstrated a significant growth inhibition of MCF-7 breast carcinoma cells upon exposure to ERS inducers alone. Results suggested that when ERS inducers are used in combination, their efficacy is enhanced as 50 percent inhibitory concentrations were considerably lower in combination as opposed to when used alone. The present study is consistent with previous studies with geldanamycin, and was the 1st to investigate the effects of geldanamycin, thapsigargin and tunicamycin in combination and with reference to P-gp efflux activity. Results suggested that in combination, efflux activity may be reduced, and efficacy may be enhanced. To enhance efficacy would be a major breakthrough in cancer drug discovery and development-targeting specific populations of cancer cells and reducing ERS-induced toxicity to normal cells and vital organs.
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McCarrick, Jessica Anne. "Differential Regulation of Steroid Receptors in Breast Cancer by the Rho GEF Vav3." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_theses/124.
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Recently reported data demonstrate that Vav3, a Rho Guanine Nucleotide Exchange Factor (Rho GEF) is overexpressed in breast tumors, coexpressed with ER, necessary for proliferation in breast cancer cells, and predictive of response to neoadjuvant endocrine therapies in patients with ER+ tumors. Such data beg the question as to what roles Vav3 plays in modulation of steroid receptor activity in breast cancer and in resistance to current hormonal therapies. Using reporter assays, I provide novel evidence that Vav3 potentiates Estrogen Receptor activity and represses Androgen Receptor activity in breast cancer cells. Vav3 potentiates ligand-dependent estrogen receptor activity in the MCF-7. A truncated, constitutively active form of Vav3, caVav3 potentiates ligand dependent ER activity in both MCF-7 and T47D. Vav3 activates Rho GTPases through its GEF domain. ER potentiation by caVav3 is dependent upon GEF activity. A caVav3 mutant with defective GEF function represses basal and ligand-mediated ER activity in T47D. Although other studies have shown that Vav3 could activate various Rho GTPases, only constitutively active Rac1 mutants potentiated ER activity in both cell lines. Contrastingly, reporter assays were used to show that caVav3 inhibits ligand-mediated AR activity in the AR+ T47D cell line by both R1881 and DHT stimulation. caVav3-mediated repression of AR activity is GEF-dependent, as caVav3 GEF mutants potentiate AR activity. Constitutively active forms of Rho GTPases were found to repress AR activity to different extents, but R1881-mediated AR activity was only significantly repressed by caCdc42. My studies of the effect of androgens on AR protein by western blot show that androgens downregulate AR protein in the highly Vav3 positive T47D cell line. Previous studies have demonstrated that androgens stabilize AR protein in MCF-7, and I now provide evidence that overexpression of Vav3 or caVav3 reverses hormone-mediated AR protein stabilization in MCF-7. These data are especially relevant given recently published data that decreased AR protein levels contributed to failure of response to MPA in patients with metastatic breast cancer. Further breast cancer studies may prove Vav3 to be a potential drug target in hormone dependent, hormone independent, and metastatic disease.
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Chaves, Catarina Alexandra da Silva. "Mechanisms of regulation of P-glycoprotein and breast cancer resistance protein at the blood-brain barrier : focus on the role of morphine, and P-glycoprotein activation." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCB162/document.
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La barrière hémato-encéphalique (BHE) représente la principale interface d'échange moléculaire entre la circulation sanguine et le système nerveux central (SNC), où elle joue un rôle essentiel sur le contrôle du passage bidirectionnel de composés endogènes et exogènes. À la BHE, la P-glycoprotéine (P-gp) et Breast Cancer Resistance Protein (BCRP) sont les transporteurs d’efflux ABC les plus importants, empêchant l'entrée de composés toxiques, des médicaments et des xénobiotiques circulant dans le sang dans le cerveau. Il y a un intérêt croissant pour la compréhension des mécanismes moléculaires sous-jacents à la modulation de l’expression et de la fonction de la P-gp et BCRP, afin de pouvoir contrôler l'accumulation de substances neurotoxiques dans le SNC et de surmonter les phénomènes de pharmaco-résistance. Des études récentes ont montré que la morphine, elle-même un substrat de la P-gp, est impliquée dans l’augmentation de l'expression de la P-gp, qui peuvent contribuer à sa faible pénétration dans le cerveau et pour le développement de la tolérance. Cependant, le mécanisme sous-jacent à l’induction de la P-gp par la morphine, bien comme son rôle sur l'expression de BCRP était inconnu. Des rats ont été utilisés comme modèle animal pour l'étude de l'amplitude et la cinétique de la modulation de la P-gp et Bcrp à la BHE, après un traitement morphinique subchronique, en utilisant un protocole d’escalade de doses. Des microvaisseaux cérébraux isolés ont été utilisés comme modèle pour étudier la BHE, et les contenus en P-gp et Bcrp après le traitement in vivo, tandis que la lignée cellulaire hCMEC/D3 a parfois été utilisé pour des études complémentaires. Nos résultats ont montré qu’un régime subchronique de traitement à la morphine pendant 5 jours a induit la P-gp et Bcrp 12 à 24 heures après la dernière dose de morphine, un effet qui n'a pas été enregistrée lors des précédentes temps de sacrifices des animaux, ni avec une traitement aigue à la morphine. Le traitement des animaux avec un antagoniste de du récepteur glutamatergique NMDA, ou avec un inhibiteur de la COX-2 a aboli l’induction protéique de la P-gp et Bcrp par la morphine-subchronique, ce qui suggère que les deux facteurs sont impliqués dans l’up-régulation morphine-dépendante de la P-gp et BCRP. Sachant que l’induction a été enregistrée seulement à partir de 12h après la dernière dose de morphine, nous avons examiné si elle était un effet direct de l'exposition continue à la morphine, ou plutôt une conséquence du sevrage à la morphine développé après l'arrêt du traitement. Les rats ont été traités soit avec une perfusion constante de morphine (5 jours), soit avec deux schémas chroniques de morphine lorsque le sevrage a été précipité par l'administration de naloxone: un régime de doses croissantes (5 jours) ou un régime de doses constantes de morphine. La perfusion en continue de morphine n'a pas changé les niveaux de P-gp et Bcrp dans les microvaisseaux cérébraux de rat, et du coup n'a pas une conséquence directe sur la cascade de régulation de ces transporteurs à la BHE. Le sevrage provoqué par la naloxone a augmenté les niveaux d’ARNm pour le Mdr1a et Bcrp, mais l'expression et de l'activité protéiques sont restées inchangées après l'administration de naloxone. Cette disparité peut être dû soit à un effet de la régulation post-traductionnelle, soit à l’action de la naloxone dans des récepteurs non-opioïdes, qui peut entraver l’induction de la P-gp et Bcrp. Par la suite, on a fait un large screening de l'expression de plusieurs récepteurs de neurotransmetteurs chez la BHE de rat, beaucoup d'entre eux impliqués dans la signalisation inflammatoire, et qui peut jouer un rôle dans la modulation de ces transporteurs ABC. (...)The blood-brain barrier (BBB) is the main interface of molecular exchange between the bloodstream and the central nervous system (CNS), where it plays an essential role on the control over the bi-directional passage of endogenous and exogenous compounds. At the BBB, P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are the most important ABC drug efflux transporters preventing the entry into the brain of toxic compounds, drugs and xenobiotics circulating in the blood. There is increasing interest in understanding the molecular mechanisms underlying the modulation of P-gp and BCRP expression and function in order to control CNS accumulation of neurotoxicants and to overcome pharmacoresistance phenomena. Recent studies showed that morphine, itself a substrate of P-gp, is implicated in the up-regulation of P-gp expression, which may contribute to its poor brain penetration and tolerance. However, it was unknown the mechanism underlying P-gp induction by morphine and its role on BCRP expression. Rats were used as an animal model for the study of the amplitude and the kinetics of the modulation of P-gp and Bcrp expressions at the BBB following a subchronic morphine treatment, in an escalating morphine dose regimen. Freshly isolated rat brain microvessels were used as BBB model to study P-gp and Bcrp contents following the in vivo treatment, while the hCMEC/D3 cell line was occasionally used for complementary studies. Our results demonstrated that a 5-day subchronic morphine regimen up-regulated both P-gp and Bcrp 12 to 24h after the last dose of morphine, which was not registered at earlier time-points of animal sacrifice, nor with a single dose of morphine. The animal treatment with a glutamatergic NMDA receptor antagonist, or a COX-2 inhibitor abolished the subchronic morphine-induced P-gp and Bcrp protein up-regulation, 24h after the last dose of morphine, suggesting that both are implicated in the morphine-dependent P-gp and Bcrp up-regulation. Since the registered up-regulation only occurred from 12h after the last dose of morphine-onwards, we investigated whether it was a direct effect of continued exposure to morphine, or rather a consequence of the morphine withdrawal developed after discontinuation of treatment. Rats were treated either with a constant morphine infusion (5 days), or two chronic morphine regimens where withdrawal was precipitated by naloxone administration: an escalating dose (5 days) or a constant dose morphine regimen followed by a withdrawal period (2 days) and resume of the treatment for 3 additional days. Continuous i.v. morphine did not change P-gp and Bcrp levels in rat brain microvessels, it does not have a direct consequence on the cascade of regulation of these transporters at the BBB. Naloxone-precipitated withdrawal after escalating or chronic morphine dose regimen increased Mdr1a and Bcrp mRNA levels, but protein expression and activity remained unchanged after naloxone administration. This latter result discrepancy may be due to posttranslational regulation or naloxone action at non-opioid receptors hampering P-gp and Bcrp up-regulation. Subsequently, we did a large screening of the expression of several neurotransmitter receptors at the rat BBB, many of them implicated in the inflammatory cell-cell signaling, and which may have a role in the modulation of these ABC transporters. Also, we compared two different approaches of isolation of rat brain microvessels, mechanical dissection and enzymatic digestion, to assess which yield the purest microvessel fraction for the BBB study. The enzymatic digestion provided the highest enrichment of endothelial cells and pericytes, and the least contamination with astrocyte and neuron markers. (...)
A barreira hemato-encefálica (BHE) representa a principal interface entre a corrente sanguínea e o sistema nervoso central (SNC), desempenhando um papel essencial no controlo da passagem sangue-cérebro de diversos compostos endógenos e exógenos. A glicoproteina P (P-gp) e a proteína de resistência ao cancro da mama (BCRP) são os principais transportadores de efluxo da família ABC presentes ao nível da BHE, limitando a passagem cerebral de compostos tóxicos, fármacos e xenobióticos circulantes na corrente sanguínea. Actualmente, regista-se um crescente interesse na comunidade científica para a melhor compreensão dos mecanismos moleculares subjacentes à modulação quer da expressão quer da função da P-gp e BCRP, no sentido de desenvolver medidas mais eficazes quer para prevenção da acumulação de compostos neurotóxicos no SNC, quer para superar fenómenos de farmacorresistência associados à terapêutica. Estudos recentes evidenciam que a morfina, por si só um substrato da P-gp, está envolvida na indução da expressão da P-gp, o que poderá contribuir para a sua menor penetração cerebral, bem como para o desenvolvimento de tolerância. No entanto, não se conhece o mecanismo subjacente a tal indução da P-gp pela morfina, nem o seu eventual papel na expressão da BCRP. Com efeito, na condução da presente dissertação, realizamos um estudo da amplitude e a cinética da regulação da expressão da P-gp e BCRP ao nível da BHE na sequência de um tratamento subcrónico com morfina, em regime de doses crescentes, usando o rato como modelo animal. Para o efeito, foram isolados os capilares cerebrais dos animais sujeitos a tratamento, in vivo, enquanto que a linha celular hCMEC/D3 foi ocasionalmente utilizada para estudos complementares. Os nossos resultados demonstraram que um tratamento subcrónico com morfina (5 dias) foi capaz de induzir tanto a P-gp como a Bcrp 12 a 24 horas após a última dose de morfina administrada, mas não para tempos de sacrifício anteriores, bem como tal indução não foi registada quando a morfina foi administrada de forma aguda. O tratamento animal com um antagonista do receptor glutamatérgico NMDA, ou com um inibidor da COX-2 anulou este efeito de indução da P-gp e Bcrp pela administraçãosubcrónica de morfina, o que sugere o envolvimento destes dois componentes na indução da P-gp e Bcrp dependente da morfina. Uma vez que este aumento da expressão só surgiu a partir de 12h após a última dose de morfina, decidimos investigar se tal seria um efeito direto da exposição continuada à morfina, ou por outro lado, uma consequência do síndrome de abstinência à morfina, desenvolvido após a descontinuação do tratamento. Desta forma, os animais foram tratados por um lado com uma infusão contínua de morfina (5 dias), ou sujeitos a dois diferentes regimes de exposição crónica à morfina, após os quais o síndrome de abstinência foi provocado pela administração de naloxona. A administração de morfina em contínuo, via i.v., não alterou os níveis de P-gp e BCRP nos capilares cerebrais de rato, o que indica a ausência de uma consequência directa da morfina na cascata de regulação destes transportadores ao nível da BHE. O síndrome de abstinência opióide provocado pela naloxona aumentou os níveis de mRNA Mdr1a e Bcrp, mas tanto a expressão e atividade proteicas mantiveram-se inalteradas após a administração de naloxona. Esta discrepância de resultados pode-se dever ou a um regulamento pós-translacional, ou a uma acção inespecífica da naloxona em receptores não opiáceos, impedindo a indução da P-gp e Bcrp. Num outro estudo, foi feito um screening da expressão de vários receptores de neurotransmissores na BHE de rato, muitos deles envolvidos na sinalização célula-célula em processos inflamatórios, e que podem ter um papel na modulação destes transportadores ABC. (...)
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Maxwell, Pamela Joan. "Insulin-like growth factor binding protein secretion by human breast cancer cell lines : changes associated with the development of anti-oestrogen resistance and oestrogen independence." Thesis, Queen's University Belfast, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268215.
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Gannon, Brian Robert. "The role of cAMP-dependent protein kinase in the expression and function of p-glycoprotein and other molecules implicated in drug resistance in adriamycin-resistant MCF-7 human breast cancer cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0018/MQ46481.pdf.
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Bauer, Stefanie [Verfasser], and Armin [Akademischer Betreuer] Buschauer. "Quinoline carboxamides as modulators of Breast Cancer Resistance Protein (ABCG2): Investigations on potency, selectivity, mechanism of action, cytotoxicity, stability and drug-like properties / Stefanie Bauer. Betreuer: Armin Buschauer." Regensburg : Universitätsbibliothek Regensburg, 2014. http://d-nb.info/1048729540/34.
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Peña, Solórzano Diana Catherine [Verfasser], Oliver [Akademischer Betreuer] Reiser, Burkhard [Akademischer Betreuer] Koenig, Rodrigo [Akademischer Betreuer] Abonia, and Claudia [Akademischer Betreuer] Rubiano. "New Analogs of Tariquidar: Synthesis, Characterization and Evaluation of their Inhibitory Activity against Breast Cancer Resistance Protein (ABCG2) / Diana Catherine Peña Solórzano ; Oliver Reiser, Burkhard Koenig, Rodrigo Abonia, Claudia Rubiano." Regensburg : Universitätsbibliothek Regensburg, 2018. http://d-nb.info/1160086311/34.
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Reipas, Kristen May. "Inhibiting p90 ribosomal S6 kinase (RSK)/Y-box binding protein-1 (YB-1) signaling is a novel targeted therapeutic strategy with the ability to overcome drug resistance in triple-negative breast cancer." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44616.
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Despite advances in treating breast cancer, disease recurrence rates remain high and secondary tumors are often refractory to chemotherapy. Currently, the treatment for triple-negative breast cancer (TNBC) relies upon conventional chemotherapeutics as no targeted therapies are available. Although these tumors initially respond well, they paradoxically have the highest relapse rates. Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor abundantly expressed in TNBC (~70% of patients) and associated with disease relapse. It is activated predominantly by phosphorylation via p90 ribosomal S6 kinase (RSK). Once activated YB-1 up-regulates the tumor-initiating cell (TIC) marker, CD44 and promotes drug resistance. These data suggest that blocking YB-1’s activation via RSK inhibition may suppress growth and attenuate the development of chemoresistance in TNBC.
Through an unbiased, functional viability screen comparing breast cancer subtypes, we identified RSK2 as a novel target for TNBC. Pharmacological or siRNA inhibition of RSK2 blocks activation of YB-1, which subsequently decreases growth in TNBC cell lines and delays tumor initiation in immunocompromised mice. Contrary to most conventional chemotherapies, inhibiting RSK/YB-1 signaling eliminates the CD44⁺/CD24‾ cell fraction rather than enriching for it. In an effort to identify novel RSK inhibitors, we screened “off-patent” compounds and identified the flavonoid, luteolin, as a RSK inhibitor. We validated that luteolin inhibits RSK in cell-free assays and further demonstrated it blocks the RSK/YB-1/Notch4 signaling pathway. Luteolin phenotypically mirrored the effects of established RSK inhibitor, BI-D1870, and suppressed growth in TNBC (including CD44⁺/CD24‾-sorted cells) providing further support for the use of RSK inhibitors to treat this subtype. Finally, we demonstrate that cells that survive standard-of-care chemotherapeutics (paclitaxel and epirubicin) exhibit elevated RSK/YB-1 signaling. Inhibiting this pathway sensitizes TNBC to chemotherapy and reduces the residual cell burden. Importantly, RSK inhibition also demonstrates efficacy against a multidrug resistant cell line and primary, drug-refractory TNBC. When taken together, our data identify RSK as a promising target for the treatment of TNBC. RSK inhibition has the unique ability to eliminate CD44⁺/CD24‾cells and overcome broad-spectrum chemoresistance by blocking activation of YB-1 and as such holds potential to reduce relapse in this aggressive subtype.
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Englund, Gunilla. "Interindividual Variability of Drug Transport Proteins : Focus on Intestinal Pgp (ABCB1) and BCRP (ABCG2)." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis: Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6127.
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Pedersen, Jenny M. "ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury." Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-205355.
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Membrane transport proteins are known to influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. At the onset of this thesis work, only a few structure-activity models, in general describing P-glycoprotein (Pgp/ABCB1) interactions, were developed using small datasets with little structural diversity. In this thesis, drug-transport protein interactions were explored using large, diverse datasets representing the chemical space of orally administered registered drugs. Focus was set on the ATP-binding cassette (ABC) transport proteins expressed in the canalicular membrane of human hepatocytes. The inhibition of the ABC transport proteins multidrug-resistance associated protein 2 (MRP2/ABCC2) and bile salt export pump (BSEP/ABCB11) was experimentally investigated using membrane vesicles from cells overexpressing the investigated proteins and sandwich cultured human hepatocytes (SCHH). Several previously unknown inhibitors were identified for both of the proteins and predictive in silico models were developed. Furthermore, a clear association between BSEP inhibition and clinically reported drug induced liver injuries (DILI) was identified. For the first time, an in silico model that described combined inhibition of Pgp, MRP2 and breast cancer resistance protein (BCRP/ABCG2) was developed using a large, structurally diverse dataset. Lipophilic weak bases were more often found to be general ABC inhibitors in comparison to other drugs. In early drug discovery, in silico models can be used as predictive filters in the drug candidate selection process and membrane vesicles as a first experimental screening tool to investigate protein interactions. In summary, the present work has led to an increased understanding of molecular properties important in ABC inhibition as well as the potential influence of ABC proteins in adverse drug reactions. A number of previously unknown ABC inhibitors were identified and predictive computational models were developed.
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Schmidt, Anja. "Das humane Y-Box-Protein YB-1 und seine Bedeutung für die Prognose und den Therapieerfolg bei Mammakarzinom." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2003. http://dx.doi.org/10.18452/14995.
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Einer der Gründe für das Scheitern derzeitiger Behandlungsmethoden beim Brustkrebs ist die Resistenz gegenüber der angewandten Chemotherapie. Eine große Rolle bei der Entstehung der Multiplen Medikamentenresistenz spielt das MDR1-Gen und sein Genprodukt, das P-Glykoprotein. Das Y-Box-Protein YB-1 reguliert die Expression des MDR1-Gens; eine Überexpression und nukleäre Lokalisation von YB-1 geht im Brustkrebs mit einer gesteigerten P-Glykoprotein Expression einher. In dieser Arbeit wurden Gewebeproben von 83 Brustkrebspatientinnen auf eine YB-1 Überexpression im Tumor und im peritumoralen Epithel untersucht. YB-1 wurde mittels der immunhistochemischen APAAP-Methode an Formalin-fixierten, in Paraffin eingebetteten Brustkrebsgewebeproben nachgewiesen. Die klinische Relevanz der YB-1 Expression wurde untersucht, indem sie mit dem klinischen Verlauf in einem mittleren Beobachtungszeitraum von 61 Monaten und etablierten biologischen Tumorfaktoren wie Lymphknotenstatus, histologisches Grading, Tumorgröße, Hormonrezeptorstatus, uPA und PAI-1 verglichen wurde. In der Kohorte der Patientinnen mit einer postoperativen adjuvanten Chemotherapie zeigte sich eine 5-Jahres-Rezidivrate von 68 % bei einer hohen YB-1 Expression im Tumor und eine Rückfallrate von 39 % bei einer niedrigen YB-1 Expression. Unter Beachtung auch der YB-1 Expression im peritumoralen Epithel konnte ein noch größerer Unterschied hinsichtlich der 5-Jahres-Rezidivrate festgestellt werden. Diese betrug bei Patientinnen mit einer hohen YB-1 Expression 66 %, während bei Patientinnen mit einer niedrigen YB-1 Expression im Nachbeobachtungszeitraum kein Rezidiv festgestellt wurde. Bei der Gegenüberstellung der 5-Jahres-Rezidivraten in der Kohorte der Patientinnen ohne Zytostatikatherapie zeigte sich eine Rückfallrate von 30 % bei einer hohen YB-1 Expression und eine Rückfallrate von 0 % bei einer niedrigen YB-1 Expression. Eine hohe YB-1 Expression war demnach in beiden Kohorten mit einer schlechteren klinischen Prognose assoziiert. Das Ergebnis in der Gruppe der Patientinnen ohne postoperative Chemotherapie zeigt, dass YB-1 mit der Tumoraggressivität beim Brustkrebs korreliert. Eine Korrelation zwischen der YB-1 Expression und den etablierten prognostischen Faktoren Lymphknotenstatus, Tumorgröße und histologisches Grading konnte nicht festgestellt werden. Es wurde jedoch eine signifikante negative Korrelation zwischen der YB-1 Expression und dem Hormonrezeptorstatus und eine positive Korrelation zwischen YB-1 und den Faktoren uPA und PAI-1 gefunden. In dieser Arbeit wurde gezeigt, dass YB-1 eine klinische Relevanz besitzt mit Hinblick sowohl auf eine prognostische als auch eine prädiktive Bedeutung bei der Identifikation von Hoch-Risiko-Patientinnen im Brustkrebs in Ab- und Anwesenheit einer postoperativen Chemotherapie.Intrinsic or acquired resistance to chemotherapy is one of the reasons for failure of current treatment regimens in breast cancer patients. P-glycoprotein and its gene mdr1 plays a major role in the development of a multi-drug resistant tumor phenotype. The Y-box protein YB-1 regulates the expression of mdr1. In human breast cancer, overexpression and nuclear localization is associated with upregulation of P-glycoprotein. In this study, tissues of 83 breast cancer patients have been analyzed with regard to YB-1 overexpression in tumor tissue and in surrounding benign breast epithelial cells. YB-1 has been detached by the immunohistochemical APAAP-method using formalin-fixed, paraffin-embedded breast cancer tissues. Clinical relevance of YB-1 expression was analyzed by comparing it with clinical outcome after a median follow-up of 61 months and with tumor biological factors lymph-node status, tumor size, histological grading, hormone-receptor status and the factors uPA and PAI-1. In patients who received postoperative chemotherapy, the 5-year-relapse rate was 68% in patients with high YB-1 expression in tumor cells and 39% in patients with low expression. With regard to YB-1 expression in surrounding benign breast epithelial cells, the 5-year-relapse rate was 66% in patients with high YB-1 expression whereas in patients with low expression no relapse has been observed so far. YB-1 thus indicates clinical drug resistance in breast cancer. In patients who received no chemotherapy, the 5-year-relapse rate was 30% in patients with high YB-1 expression whereas in patients with low YB-1 expression no relapse occurred. YB-1 thus correlates with breast cancer aggressiveness. In both groups high YB-1 expression was associated with poor clinical outcome. A correlation between YB-1 and tumor biological factors lymph-node status, tumor size and histological grading has not been found. But a significant negative correlation has been observed between YB-1 and hormone-receptor status and a positive correlation between YB-1 and uPA and PAI-1. This dissertation could show the clinical relevance of YB-1 with regard to a prognostic and predictive significance by identifying a high-risk group of breast cancer patients both in presence and absence of postoperative chemotherapy.
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Tournier, Nicolas. "Transport cérébral de drogues et radiotraceurs par les proteines ABC." Paris 5, 2009. http://www.theses.fr/2009PA05P637.
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Au cours de ce travail, différents modèles d’études in vitro et in vivo ont été développés afin de déterminer les mécanismes et connaître l’influence de transporteurs appartenant à la famille des ABC protéines (ATP Binding Cassette). La P-glycoprotéine (P-gp, ABCB1) et la Breast Cancer Resistance Protein (BCRP, ABCG2) sont deux transporteurs ABC exprimés au niveau de la barrière hémato-encéphalique (BHE) capables de moduler le passage cérébral de nombreux médicaments et pouvant ainsi introduire une variabilité pharmacocinétique et clinique de ses substrats. Ainsi, l’interaction de drogues, de certains de leurs métabolites et molécules de substitutions a été étudiée avec des modèles cellulaires de la P-gp et de la BCRP humaines. La P-gp module de manière importante le transport de la norbuprénorphine, seul métabolite actif de la buprénorphine (ratio de transport ~11 fois) et de façon modéré pour la méthadone (ratio de transport ~2 fois). Parmi ces composés, l’ibogaïne, un produit en cours d’évaluation dans la substitution aux drogues a été sélectionné afin de pouvoir développé une nouvelle stratégie de marquage par le 99mTc-tricarbonyle émetteur gamma pour la neuro-imagerie par émission monophotonique (TEMP). Ainsi, le radiomarquage et la purification du complexe synthétisé (99mTc-(CO)3-ibogaïne) ont été réalisés permettant l’étude du transport par perfusion cérébrale in situ chez la souris et sur modèles cellulaires. Ainsi, une faible extraction cérébrale non restreinte au niveau de la BHE par la P-gp mais liée à sa plus faible lipophilie et à la présence d’une charge cationique interagissant significativement avec le potentiel de dipôle membranaire sont des facteurs intervenant sur cette perméabilité restreinte. En effet, notre étude sur les radiotraceurs TEMP technétiés a montré que la P-gp et surtout le potentiel du dipôle membranaire pouvaient fortement restreindre le passage cellulaire et cérébral pour certains dérivés téchnétiés cationiques tels que le 99mTc-sestamibi, à la différence de dérivés non chargés. Ces modèles ont ensuite été adaptés pour l’étude du transport de plusieurs radiotraceurs utilisés en tomographie par émission de positons (TEP) pour permettre d’apprécier la variabilité de leur distribution cérébrale liée à la P-gp et à la BCRP. Dans cette étude, il est montré que certains radiotraceurs sont des substrats de la P-gp et/ou de la BCRP tout en ayant la capacité de franchir et de se distribuer dans le parenchyme cérébralIn this work, several in vitro and in vivo models have been developed to study the pharmacological impact of P-glycoprotein (P-gp, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2), two ABC transporters (ATP Binding Cassette) expressed at the blood-brain barrier (BBB). These transporters are able to influence the brain uptake of their substrates with significant pharmacological and clinical impact. Thus, interaction of 14 drugs-of-abuse and maintenance treatments or their main metabolites with human P-gp and BCRP were studied in vitro. Norbuprenorphine, which is the active metabolite of buprenorphine (transport ratio ~11 fold), and, in a lesser extent methadone (transport ratio ~2 fold), appeared to be specifically transported by human P-gp. Among tested drugs, psychoactive ibogaine was radiolabeled using 99mTc-tricarbonyl core, as a new radiotracer for SPECT imaging (single photon emitting computed tomography). 99mTc-(CO)3-ibogaine was synthesized and purified. Its brain transport was studied in vivo using the in situ brain perfusion technique and in vitro. As previously reported for 99mTc-sestamibi, 99mTc-(CO)3-ibogaine low brain uptake seems to be due to poor lipophilicity and cationic charge interacting with membrane dipole potential, contrary to some uncharged and lipophilic 99mTc-compounds like 99mTc-HMPAO. However, 99mTc-(CO)3-ibogaine does not seem to be transported by P-gp. Then, these models have been adapted to study PET (positron emitting tomography) tracers transport by human P-gp and BCRP. Some of these tracers, with significant brain uptake, appeared to be transported by P-gp or BCRP
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Matsson, Pär. "ATP-Binding Cassette Efflux Transporters and Passive Membrane Permeability in Drug Absorption and Disposition." Doctoral thesis, Uppsala University, Department of Pharmacy, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8371.
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Transport into and across the cells of the human body is a prerequisite for the pharmacological action of drugs. Passive membrane permeability and active transport mechanisms are major determinants of the intestinal absorption of drugs, as well as of the distribution to target tissues and the subsequent metabolism and excretion from the body. In this thesis, the role of ATP-binding cassette (ABC) transporters and passive permeability on drug absorption and disposition was investigated. Particular emphasis was placed on defining the molecular properties important for these transport mechanisms.
The influence of different transport pathways on predictions of intestinal drug absorption was investigated using experimental models of different complexity. Experimental models that include the paracellular pathway gave improved predictions of intestinal drug absorption, especially for incompletely absorbed drugs. Further, the inhibition of the ABC transporters breast cancer resistance protein (BCRP/ABCG2) and multidrug-resistance associated protein 2 (MRP2/ABCC2) was experimentally investigated using structurally diverse datasets that were representative of orally administered drugs. A large number of previously unknown inhibitors were identified among registered drugs, but their clinical relevance for drug-drug interactions and drug-induced toxicity remains to be determined. The majority of the inhibitors affected all three major ABC transporters BCRP, MRP2 and P-glycoprotein (P gp/ABCB1), and these multi-specific inhibitors were found to be enriched in highly lipophilic weak bases.
To summarize, the present work has led to an increased knowledge of the molecular features of importance for ABC transporter inhibition and passive membrane permeability. Previously unknown ABC transporter inhibitors were identified and predictive computational models were developed for the different drug transport mechanisms. These could be valuable tools to assist in the prioritization of experimental efforts in early drug discovery.
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Lewis, Ian. "Expression and role of protein kinase C isoforms in tamoxifen resistant breast cancer." Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/56034/.
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The development of resistance to anti-oestrogenic therapies such as tamoxifen is a serious clinical problem in the treatment of breast cancer. A specific model of Tamoxifen resistance has been developed in the Tenovus laboratories by maintaining MCF-7 breast cancer cells in Tamoxifen (10" M) for 4-6 months. The resistant cells that arise from these cultures are termed TAM-R cells. We wished to utilize these cells to test the hypothesis that resistance to tamoxifen is due to changes in protein kinase C (PKC) isoform expression. Initially we investigated PKC expression in the TAM-R cells and demonstrated that they express significantly more basal and activated protein kinase C (PKC)-a and 8 than wild type MCF-7 cells. To test the implications of this observation, we wished to specifically and selectively ablate these PKCs in the TAM-R cells and assess the outcomes. The limitations of pharmacological inhibitors such as bisindolylmaleimide LX (Ro31-8220) and Rottlerin were highlighted by our studies which concurs with a general discontent in the current literature over their specificity and efficacy. We therefore utilised RNAi and adenovirus mediated molecular technologies to modulate the PKC-ct and PKC-8 isoform expression profile in the MCF-7 and TAM-R cell lines. Using both RNAi and adenoviral infection of dominant negative mutants we demonstrated that down regulation of PKC-a and PKC-8 blocks both growth factor and oestradiol induced growth in MCF-7 and TAM-R cells. Thus PKC-a and 8 must play an important role in the mitotic pathways utilised by tamoxifen resistant breast cancer cells. Moreover overexpressing PKC-a and 8 in MCF-7 cells allowed them to acquire resistance to tamoxifen and possibly even led to tamoxifen becoming agonistic for these cells, suggesting a role for these isoforms of PKC in inducing the tamoxifen resistant phenotype.
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Strong, Rachael F. "A comparative proteomic analysis of mitochondrial proteins from drug susceptible and drug resistant human MCF-7 breast cancer cells." College Park, Md. : University of Maryland, 2005. http://hdl.handle.net/1903/2870.
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Rahbar, Amir Mikel. "Proteomic analysis of plasma membrane proteins from drug susceptible and drug resistant breast cancer cell lines." College Park, Md. : University of Maryland, 2004. http://hdl.handle.net/1903/1981.
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Thesis (Ph. D.) -- University of Maryland, College Park, 2004.Thesis research directed by: Biochemistry. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Manciu, Liliana. "Structural characterization of intermediate states occuring during chemotherapeutic agents transport mediated by Multidrug resistance protein 1 (MRP1), a protein involved in multidrug resistance of cancer cells." Doctoral thesis, Universite Libre de Bruxelles, 2003. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211217.
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Fu, Zongming. "Comparative proteomics studies of soluble nuclear proteins of drug susceptible and resistant human breast cancer MCF-7 cells." College Park, Md. : University of Maryland, 2004. http://hdl.handle.net/1903/1945.
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Thesis (Ph. D.)--University of Maryland, College Park, 2004.Thesis research directed by: Chemistry. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Winter, Aaron. "Protein metabolism and insulin resistance in non-small cell lung cancer cachexia." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=97084.
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Cancer cachexia is characterized by weight loss and insulin resistance. Previous work has shown blunted protein anabolism in insulin resistant conditions. This study tested whether hyperaminoacidemia with hyperinsulinemia elicits blunted whole-body protein anabolism in cachectic non-small cell lung cancer (NSCLC). Whole-body [13C]leucine and [3H]glucose kinetics were assessed in 8 NSCLC patients and 10 age and weight-matched controls during a euglycemic, hyperinsulinemic, clamp with isoaminoacidemia (Iso-AA), followed by hyperaminoacidemia (Hyper-AA). Glucose utilization increased from Iso-AA to Hyper-AA but was lower in NSCLC patients. During Iso-AA, protein breakdown decreased and synthesis was unchanged resulting in positive net balance that was lower in NSCLC patients. During Hyper-AA, synthesis increased but breakdown was unchanged resulting in increased net balance in both groups. In summary, weight-losing NSCLC patients demonstrate insulin resistance of whole-body glucose and protein metabolism. Physiologic hyperaminoacidemia normalized their anabolic response to that of controls and did not impair insulin sensitivity of glucose.La perte de poids et la résistance à l'insuline caractérisent la cachexie due au cancer. Un anabolisme protéique amoindri a été démontré dans des conditions d'insulino-résistance. Cette étude a évalué si l'hyperaminoacidemie et l'hyperinsulinemie résultent en un défaut de l'anabolisme protéique corporel dans la cachexie due au cancer du poumon « non à petites cellules » (NSCLC). La cinétique des protéines ([13C]leucine) et du [3H]glucose corporels ont été évalués chez 8 patients avec NSCLC et 10 hommes en santé, d'âge et de poids similaires, à l'aide du clamp hyperinsulinique, euglycémique, isoaminoacidémique (Iso-AA), suivi d'une hyperaminoacidémie (Hyper-AA). L'utilisation du glucose a augmenté entre Iso-AA et Hyper-AA, mais il était plus bas chez les patients NSCLC. Pendant Iso-AA, la dégradation des protéines a diminué et la synthèse n'a pas changé, résultant en une balance positive moindre chez les NSCLC. En Hyper-AA, la synthèse a augmenté, mais la dégradation n'a pas changé, ce qui a augmenté davantage la balance positive, dans les deux groupes. En résumé, les patients NSCLC perdant du poids ont démontré une résistance du métabolisme glucidique et protéique à l'insuline. L'hyperaminoacidémie a normalisé leur réponse anabolique à celle des contrôles sans affecter la sensibilité du glucose à l'insuline.
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Abd, Latip Normala. "LARP1, an mRNA binding protein involved in cancer progression & platinum resistance." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/39469.
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LARP1 is a novel protein that was first identified in Drosophila where it was shown to be required for embryogenesis, spermatogenesis and cell cycle progression. LARP1 is 'La-related protein' by virtue of its La domain and RRM motif, common to all La proteins. Unlike the other members of LARP family, LARP1 also carries a conserved C terminal domain; the tandem DM15 repeat-containing region which is of unknown function, although it has been proposed to be involved in mRNA binding. LARP1 has been shown previously in our lab to regulate the translation of a subset of mRNAs that encode cytoskeletal proteins, as well as the synthesis of proteins required for invasion such as ?-2 catenin, actin-gamma and matrix metalloprotease 14 (MMP-14). Also, LARP1 has been reported to interact with cytoskeletal proteins such as tubulin, keratins, actin, myosin and the cell-cell junction protein, Zona occludens1 (ZO-1) as well as the actin binding proteins: Plectin, Spectrin, Actinin and Tropomyosin and the actin-capping proteins CapZA and CapZB. In this thesis, LARP1 is demonstrated to exist in complexes with both PABP and eIF4E, colocalise within lamellipodia of the cells, and be required for migration. In histological specimens taken from women with normal cervix (normal), pre-invasive cervical intra-epithelial neoplasia (CIN) and invasive squamous cell cancer (SCC), levels of cytoplasmic LARP1 were shown to be elevated from normal to CIN and from CIN to SCC, suggesting an association between levels of cytoplasmic LARP1 and cancer progression. Morphologically, following LARP1 over-expression, there is loss cell-to-cell contact with scattering of cells away from their original clusters. Cells also acquire a spindle-like appearance, and express characteristic of mesenchymal markers, which suggest LARP1 induces epithelial mesenchymal transition (EMT). LARP1 depletion resensitises a platinum-resistant ovarian carcinoma cell line to cisplatin treatment. In this study, we show that cells with reduced LARP1 have lower expression of Mre11 but have unaltered DNA damage recognition by ?H2AX foci. LARP1 knockdown also alters BRCA2 expression and its subcellular localisation following cisplatin treatment. These findings suggest LARP1 depletion impairs the ability of the cell to efficiently repair cytotoxic DNA damage. In this thesis we show that the RNA-binding protein LARP1 is involved in cell migration, epithelial mesenchymal transition and chemotherapeutic resistance. This supports a role for LARP1 in, cancer progression, and suggests it may act as a promising new therapeutic target in cancer.
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Cochrane, Guy R. "Inhibition of the multidrug resistance-associated protein : an antisense and ribozyme approach." Thesis, University of East Anglia, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302228.
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McLaren, Susan R. A. "The generation of recombinant phage antibodies to the multiple drug resistance protein P-glycoprotein." Thesis, University of Aberdeen, 1997. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU104246.
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The generation of human antibodies to the multiple drug resistance protein, P-glycoprotein (Pgp), has been a challenge in the field of cancer chemotherapy since drug resistance was first described. Pgp was identified as being an intrinsic factor in the resistance to chemotherapeutic drugs, as its levels were found to escalate after primary drug challenges. Further investigation into the structure and function of P-glycoprotein elucidated that its activity was ATP dependent, and that it had broad spectrum specificity. In order to augment the success of chemotherapeutic treatment of patients it was deemed necessary to regulate the activity of this protein. This was possible by physical inhibition of its activity or through regulation at the genetic level. This project addresses the former of the two options, the physical inhibition of Pgp activity. It was considered that by the generation of antibodies to the extracellular regions of Pgp it would be possible to inhibit its activities. For such antibodies to be effective in the human model, the antibodies would have to bear human determinants in order that the human immune system would not attach and destroy these antibodies before they had the desired effect. Therefore it was decided that recombinant phage technology should be used. This is a system which selects single chain antibodies with human determinants from a large and diverse population of antibodies with a variety of specificities. Initially, attempts were made to generate a phage library de novo using a commercial kit designed for this purpose. However, after repeated attempts at this process, this approach was found to be beyond technical abilities, and was rejected in favour of a more rudimentary approach. Two libraries were screened for antibodies which would bind to membrane preparations from two leukaemic cell lines, CCRF CEM and CCRF CEM VLB. The former cell line was a drug-sensitive cell line which responded favourably to drug challenge, and the latter was a drug-resistant cell line which thrived in drug-rich environments. The drug-resistant cell line was derived from the drug-sensitive cell line, and was considered to be identical in all respects except drug sensitivity. Antibodies obtained from a large multicombinatorial library, the Lox library, were found to display selective binding to CCRF CEM VLB cell membranes in favour of CCRF CEM cell membranes. Antibodies were also generated to peptides representing the 6 extracellular loops of Pgp. From these selections antibodies were generated which were found to selectively bind the peptide to which they had been raised.
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Fenton, James A. L. "The relationship between protein kinases and multidrug resistance in Chinese hamster ovary cells." Thesis, University of York, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336842.
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Hagras, Muhammad A. "Overexpression of active AKT3 induces differential binding of coregulator proteins to the estrogen receptor as a possible mechanism of Tamoxifen resistance." Scholarly Commons, 2008. https://scholarlycommons.pacific.edu/uop_etds/688.
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Tamoxifen is an effective anti-estrogen for treatment of women with hormonedependent breast cancer but acquired drug resistance limits its therapeutic benefit. We have previously reported that expression of active Akt3 in MCF-7 breast cancer cells results in estrogen-independent tumors that are actually stimulated to grow after tamoxifen treatment. We hypothesize that this tamoxifen resistance may be attributed to binding of different co-regulator proteins and/or different binding affinity of these proteins to the estrogen receptor in M CF-7 cells overexpressing active Akt3 as compared to parental MCF-7 cells. We have immuno-precipitated the estrogen receptor along with bound co-regulator proteins in both cells lines after tamoxifen, estradiol, or vehicle treatment. After 2-D gel electrophoresis separation of these immuno-precipitated proteins and comparing them using PDQuest 2-D analysis software, we identified protein spots that were statistically different under the treatment conditions between the two cell lines. The isolated protein spots were subjected to MALDI-TOF mass spectrometry. By searching protein databases through the MASCOT website for protein identification, we have identified estrogen receptor co-regulator proteins that may play a potential role in tamoxifen resistance. Current studies are focused on addressing the role of differential protein binding as a possible mechanism of tamoxifen resistance in Akt3 over-expressing breast cancer cells.
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Drew, Lisa. "The relationship between protein kinase C and the multidrug resistance phenotype in human KB carcinoma cells." Thesis, University of York, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321677.
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Johansson, Senia. "Studies on Cytotoxic and Neutrophil Challenging Polypeptides and Cardiac Glycosides of Plant Origin." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5092-X/.
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Spaeth-Cook, Douglas M. Jr. "Identification of Thioredoxin-Interacting Protein as a Potential Mediator of Anoikis-Resistance in Ovarian Cancer." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1494314758133333.
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Geng, Wei, and 耿瑋. "The role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in HCC." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43224106.
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Dhillon, Jaspreet. "Y-box binding protein-1 is essential for the growth and survival of HER2 over-expressing breast cancers and mediates trastuzumab resistance by inducing CD44." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/24372.
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Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in 40% of all subtypes of invasive breast carcinomas, where its expression is correlated with relapse and poor survival. HER2 amplifications are a frequent genetic abnormality observed in approximately 25% of breast cancers where its over-expression is associated with poor clinical outcome and decreased disease free survival. We recently reported that HER2 over-expressing breast cancers are dependent on YB-1 for growth and survival. In HER2 positive tumours we implicated YB-1 in sustaining cancer cells by its involvement in the STAT3 signalling pathway. The development of trastuzumab, a targeted therapy against HER2, has provided substantial advances in the care and treatment of patients whose tumours over-express HER2. Unfortunately, the development of acquired resistance to trastuzumab remains a prevalent challenge in the treatment of patients whose tumours express HER2. Since YB-1 is also linked to drug resistance in other types of cancer, we addressed its possible role in trastuzumab insensitivity. Employing an in vivo model of acquired resistance, we demonstrated that resistant cell lines have elevated levels of P-YB-1S¹°² and its activating kinase P-RSK and that these levels are sustained following trastuzumab treatment. Further, to demonstrate the importance of YB-1 in mediating drug resistance, the expression of the active mutant YB-1S¹°²D rendered the BT474 cell line insensitive to trastuzumab. Questioning the role of tumour initiating cells (TICs) and their ability to escape cancer therapies, we investigated YB-1’s involvement in inducing the cancer stem cell marker CD44. Notably, the resistant cells expressed more CD44 mRNA and protein compared to BT474 cells, which correlated with increased mammosphere formation. Expression of YB-1S¹°²D in the BT474 cells increased CD44 protein levels, resulting in enhanced mammosphere formation. Further, exposing BT474 cells to trastuzumab selected for a resistant subpopulation enriched for CD44. Conversely, siRNA inhibition of CD44 restored trastuzumab sensitivity in the resistant cell lines. Our findings provide insight on a novel mechanism employed by tumour cells to acquire the ability to escape the effects of trastuzumab and suggest that targeting YB-1 may overcome resistance by eliminating the unresponsive TIC population, rendering the cancer sensitive to therapy.
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Geng, Wei. "The role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in HCC." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43224106.
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Vezmar, Marko. "Pharmacological effects of quinoline-related compounds in human tumour cells overexpressing the multidrug resistance protein (MRP)." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0003/MQ37175.pdf.
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MacAdams, Jacqueline. "Substrate contribution to endogenous glucose production, insulin resistance and protein metablism in non-small cell lung cancer cachexia." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104777.
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The loss of muscle mass and adipose tissue in cancer cachexia may be linked to increased rates of gluconeogenesis (GNG) and altered whole-body protein metabolism. This study measured the fractional contributions (%) of glycogen, glycerol and phophoenolpyruvate (PEP) to endogenous glucose production (EGP) using oral 2H2O in non-small cell lung cancer (NSCLC) patients and matched healthy control subjects. Additionally, 13C-leucine and 3H3-glucose tracers were used to measure whole-body protein turnover and glucose kinetics respectively during the fasting state and during a hyperinsulinemic euglycemic clamp. The rate of EGP and the fractional substrate contributions were not different between the NSCLC and control groups following a 17-hour fast. The majority of EGP came from equal contributions of PEP and glycogen, whereas glycerol contributed < 10%. NSCLC patients were insulin resistant; their lesser clamp glucose uptake was not correlated to GNG flux, but rates of protein oxidation were, indicating less protein retention.La perte de tissus musculaire et adipeux associée à la cachexie du cancer pourrait être reliée à des taux accrus de néoglucogénèse (GNG) et de turnover des protéines corporelles. Cette étude a mesuré la contribution fractionnelle (%) du glycogène, du glycérol et du phosphoénolpyruvate (PEP) à la production endogène de glucose (EGP), à l'aide du 2H2O oral chez des patients avec cancer du poumon (NSCLC) et des sujets témoins appariés. De plus, les cinétiques de protéines et de glucose ont été quantifiées à l'aide des traceurs 13C-leucine et 3H3-glucose, à jeun et durant un clamp hyperinsulinique, euglycémique. Les taux d'EGP et les contributions fractionnelles des substrats n'étaient pas différents entres les groupes NSCLC et témoins suite à un jeûne de 17 heures. Le PEP et le glycogène ont contribué également et majoritairement au EGP; le glycérol contribuant pour < 10%. Les patients avec NSCLC étaient résistants à l'insuline. Leur taux inférieurs de captation du glucose n'étaient pas corrélés avec le flux néoglucogénique, mais celui-ci était positivement relié aux taux d'oxydation des protéines, indiquant une moindre rétention.
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Nadkarni, Aditi A. "Functional analysis of the Rad51d (E233G) breast cancer associated polymorphism and a pharmacogenetic evaluation of RAD51D status." Connect to full text in OhioLINK ETD Center, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=mco1222877984.
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Dissertation (Ph.D.)--University of Toledo, 2008."In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Title from title page of PDF document. Bibliography: pages 73-77, 93-95, 109-111, 145-172.
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Startzman, Ashley N. "Inhibition of stat3 protein as an approach to sensitizing ovarian cancer cells to cisplatin." Honors in the Major Thesis, University of Central Florida, 2008. http://digital.library.ucf.edu/cdm/ref/collection/ETH/id/1143.
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This item is only available in print in the UCF Libraries. If this is your Honors Thesis, you can help us make it available online for use by researchers around the world by following the instructions on the distribution consent form at http://library.ucf.edu/Systems/DigitalInitiatives/DigitalCollections/InternetDistributionConsentAgreementForm.pdf You may also contact the project coordinator, Kerri Bottorff, at kerri.bottorff@ucf.edu for more information.Bachelors
Medicine
Molecular Biology and Microbiology