Dissertations / Theses on the topic 'Drug resistance in cancer cells'
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1
Stordal, Britta Kristina. "Regrowth resistance in platinum-drug resistant small cell lung cancer cells." Bill Walsh Cancer Research Laboratories, Royal North Shore Hospital and The University of Sydney, 2007. http://hdl.handle.net/2123/2467.
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Doctor of Philosophy (PhD)The H69CIS200 cisplatin-resistant and H69OX400 oxaliplatin-resistant cell lines developed as part of this study, are novel models of low-level platinum resistance. These resistant cell lines do not have common mechanisms of platinum resistance such as increased expression of glutathione or decreased platinum accumulation. Rather, these cell lines have alterations in their cell cycle allowing them to proliferate rapidly post drug treatment in a process known as ‘regrowth resistance’. This alteration in cell cycle control has come at the expense of DNA repair capacity. The resistant cell lines show a decrease in nucleotide excision repair and homologous recombination repair, the reverse of what is normally associated with platinum resistance. The alterations in these DNA repair pathways help signal the G1/S checkpoint to allow the cell cycle to progress despite the presence of DNA damage. The decrease in DNA repair capacity has also contributed to the development of chromosomal alterations in the resistant cell lines. Similarities in chromosomal change between the two platinum resistant cell lines have been attributed to inherent vulnerabilities in the parental H69 cells rather than part of the mechanism of resistance. The H69CIS200 and H69OX400 resistant cells are cross-resistant to both cisplatin and oxaliplatin. This demonstrates that oxaliplatin does not have increased activity in low-level cisplatin-resistant cancer. Oxaliplatin resistance also developed more rapidly than cisplatin resistance suggesting that oxaliplatin may be less effective than cisplatin in the treatment of SCLC. The resistant cell lines have also become hypersensitive to taxol but show no alterations in the expression, polymerisation or morphology of tubulin. Rather, the PI3K/Akt/mTOR pathway is involved in both platinum resistance and taxol sensitivity as both are reversed with rapamycin treatment. mTOR is also phosphorylated in the resistant cell lines indicating that platinum resistance is associated with an increase in activity of this pathway. The mechanism of regrowth resistance in the platinum-resistant H69CIS200 and H69OX400 cells is a combination of activation of PI3K/Akt/mTOR signalling and alterations in control of the G1/S cell cycle checkpoint. However, more work remains to determine which factors in these pathways are governing this novel mechanism of platinum resistance.
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Stordal, Britta. "Regrowth resistance in platinum-drug resistant small cell lung cancer cells." Connect to full text, 2006. http://hdl.handle.net/2123/2467.
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Thesis (Ph. D.)--University of Sydney, 2007.Title from title screen (viewed 10 June 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Discipline of Medicine, Faculty of Medicine. Degree awarded 2007; thesis submitted 2006. Includes bibliographical references. Also available in print form.
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Richardson, Julie. "Ovarian cancer stem-like cells and drug resistance." Thesis, University of Leeds, 2014. http://etheses.whiterose.ac.uk/8009/.
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Ovarian cancer is characterised by late diagnosis, relatively poor survival and high recurrence due to the development of multidrug resistance (MDR – resistance to various types of drug). Cancer stem-like cells (CSCs) are thought to contribute to drug resistance due to the over-expression of ABC transporters which efflux chemotherapeutic drugs. Frequently overexpressed ABC transporters include Multidrug resistance protein 1 (MRP1), P-glycoprotein (Pgp) and Breast cancer resistance protein (BCRP). No definitive stem cell marker panel has been determined for ovarian CSC detection; investigation of multiple putative stem cell markers (CD133, CD24, CD44 and Aldehyde dehydrogenase (ALDH)) may prove beneficial to the identification of these cells. All three ABC transporters are heterogeneously expressed in the ovarian cancer cell lines studied. Functional MRP1 and Pgp activity was identified utilising the Calcein-AM assay. Stem cell markers CD133 and ALDH were undetectable by western blot (WB). However small populations of ALDH expressing cells were detected using the ALDEFLUOR™ assay. Low-level CD44 was observed by WB, and confirmed by IF. RT-qPCR and microarray analysis confirmed the gene expression of all three ABC transporters and stem cell markers. A potential CSC population of high Hoechst effluxing cells, called a side population (SP) was identified. However, the viability of the SP was greatly reduced. Chemotherapeutic resistance to carboplatin, paclitaxel and doxorubicin was determined in ovarian cancer cell lines. The ovarian cancer cell line 1847 supports CSC and MDR theories, showing greater colony and spheroid formation and is most resistant to chemotherapeutics. Heterogeneous ABC transporter and stem cell marker expression was confirmed in primary samples. IHC analysis confirmed marker expression was not correlated with patient survival. Correlations were observed between MRP1 and CD44 and ALDH, CD44 and Pgp, BCRP and ALDH expression. Cells derived from patient ascites were also capable of forming colonies and spheroids, indicative of CSC properties.
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Davidson, Scott M. "Analysis of prognostic and drug resistance markers in lung cancer." Connect to e-thesis, 2007. http://theses.gla.ac.uk/101/.
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Thesis (M.D.) - University of Glasgow, 2007.M.D. thesis submitted to the Centre for Oncology and Applied Pharmacology, Cancer Research UK Beatson Laboratories, University of Glasgow, 2007. Includes bibliographical references. Print version also available.
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Anthoney, David Alan. "Defective mismatch repair and cisplatin resistance in ovarian cancer cells." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363161.
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Fung, Kwong-lam, and 馮廣林. "Chemoresistance induced by mesenchymal stromal cells on cancer cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/205639.
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Human mesenchymal stromal cells (hMSCs) are part of bone marrow micro-environment that supports hematopoiesis. However, hMSCs also enhance tumor progression and survival when they become part of the cancer micro-environment. I aimed to investigate the interaction between hMSCs and cancer cells during chemotherapy.
Firstly, I studied the interaction between hMSCs and T-lineage acute lymphoblastic leukemia (T-ALL) cells under pegylated arginase I (BCT-100) treatment. Three T-ALL cell lines were sensitive to BCT-100 but not hMSCs. Conversely, hMSCs could partly protect all T-ALL cell lines from BCT-100 induced cell death under transwell co-culture condition. Concerning the possible mechanism, the intermediate metabolite L-ornithine could not rescue most T-ALL cells from BCT-100 treatment. But the downstream L-arginine precursor, L-citrulline could partly rescue all T-ALL cells from BCT-100 treatment. Ornithine transcarbamylase (OTC) converts L-ornithine into L-citrulline. OTC expression level in hMSCs remained relatively high during BCT-100 treatment but OTC expressions in T-ALL cell lines declined drastically. It suggested that hMSCs may protect T-ALL cells against BCT-100 treatment by having sustained OTC expression. Suppression of hMSCs by vincristine (VCR) disrupted the protective effect of hMSCs to most T-ALL cells during BCT-100 treatment. This suggests that by transiently suppressing hMSCs, we may abolish the protective effect of hMSCs to T-ALL cells during BCT-100 treatment.
Then I studied the interaction between hMSCs and neuroblastoma under cisplatin treatment. Two neuroblastoma cell lines were used for both of them are cisplatin sensitive while hMSCs are cisplatin resistant. hMSCs could partly protect neuroblastoma cells from cisplatin induced cytotoxicity. On the other hand, exogenous IL-6 but not IL-8 could also partly rescue them from cisplatin induced cytotoxicity. IL-6 activated STAT3 phosphorylation dose-dependently and enhanced expression of detoxifying enzyme (glutathione S-transferase π, GST-π) in neuroblastoma. Such effect could be counteracted by anti-IL-6R neutralizing antibody tocilizumab (TCZ). However, TCZ failed to suppress hMSCs’ protection to neuroblastoma during cisplatin treatment. This suggests involvement of multiple factors. Up-regulation of serum GST-πin some hTertMSCs/neuroblastoma co-engrafted SCID mice compared to neuroblastoma engrafted mice provided a clue that GST-π might be a possible stromal-protection factor. Caffeic acid phenethyl ester (CAPE) is a known GST inhibitor after tyrosinase activation. Neuroblastoma cells expressed tyrosinase and CAPE enhanced cisplatin cytotoxicity on them, with or without hMSCs. Paradoxically, CAPE enhanced GST-πexpression with or without cisplatin treatment in neuroblastoma suggesting possible negative feedback to GST-π inhibition. However, such additive effect of CAPE to cisplatin cytotoxicity was not observed in vivo. Further delineation of the in vivo study design may help to verify the additive effect of CAPE to cisplatin cytotoxicity in vivo.
Finally, I studied the effect of apoptotic cancer cells (AC) on the immune function of hMSCs. hMSCs could phagocytose apoptotic neuroblastoma cells with respective up-regulation of many immune-mediators including two highly-expressed cytokines IL-6 and IL-8. Up-regulation of these immune-mediators may enhance immune cells chemotaxis. Further detailed investigation on the effect of AC-engulfed hMSCs to other immune cells will help us to understand the dynamic interaction between cancer cells and stromal cells during chemotherapy.published_or_final_version
Paediatrics and Adolescent Medicine
Doctoral
Doctor of Philosophy
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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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Vlerken, Lilian Emilia van. "Modulation of multidrug resistance in cancer using polymer-blend nanoparticles : thesis /." Diss., View dissertation online, 2008. http://hdl.handle.net/2047/d10017355.
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Windsor, James Brian. "Establishing a role for ecto-phosphatase in drug resistance /." Digital version accessible at:, 2000. http://wwwlib.umi.com/cr/utexas/main.
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Timme, Cindy R. "Drug Resistance Mechanisms to Gamma-secretase Inhibitors in Human Colon Cancer Cells." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4954.
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Colorectal cancer is the third leading cause of cancer-related mortality. Much progress has been achieved in combating this disease with surgical resection and chemotherapy in combination with targeted drugs. However, most metastatic patients develop drug resistance so new modalities of treatment are needed.
Notch signaling plays a vital role in intestinal homeostasis, self-renewal, and cell fate decisions during post-development and is activated in colorectal adenocarcinomas. Under debate is its role in carcinomas and metastatic disease. In theory, blocking Notch activation using gamma-secretase inhibitors (GSIs) may show efficacy alone or in combination with chemotherapy in the treatment of colon cancer.
In Chapter Three, we tested the capacity for GSIs to synergize with oxaliplatin in colon cancer cell lines and evaluated the underlying molecular mechanisms. GSI alone had no effect on colon cancer cell lines. Surprisingly, we show that GSIs blocked oxaliplatin-induced apoptosis through increased protein levels of the anti-apoptotic Bcl-2 proteins Mcl-1 and/or Bcl-xL. Restoration of apoptosis was achieved by blocking Mcl-1 and/or Bcl-xL with obatoclax (an anti-apoptotic Bcl-2 agonist) or siRNA. An unexpected result was the induction of cell death with the combination of GSI and obatoclax.
In Chapter Four, we examined the mechanism of GSI + obatoclax-mediated cell death. We found that apoptosis played a minimal role. Rather, we identified blockage of cytoprotective autophagy played a causative role. Interestingly, we also saw autophagy induction in GSI-treated cells, which could explain the insensitivity of colon cancer cells to GSI. When autophagy was blocked in GSI-treated cells, cells became sensitive to GSI and cell death was elicited. The mechanism by which induction of autophagy occurs in GSI- treated cells is an area for further research.
Overall, our work questions the validity of the use of GSIs in the treatment of colorectal cancers. We show that GSIs may block apoptosis and induce cytoprotective autophagy simultaneously, resulting in increased drug resistance and cellular survival. Whether these two cellular survival processes occurs in patients needs to be examined before GSIs can be utilized in a clinical setting. If so, these two hurdles must be overcome.
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Wang, Xuan. "Internalization of Extracellular ATP by Cancer Cells and its Functional Roles in Cancer Drug Resistance." Ohio University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1505834714683835.
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Chau, Wing-ka, and 周穎嘉. "Characterization of ovarian tumor-initiating cells and mechanisms of chemoresistance." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/197834.
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Chemoresistance remains a major clinical obstacle to effective management of ovarian cancer. Cancer stem cells (or tumor-initiating cells, TICs) have been discovered recently, and have played a pivotal role in changing the view of cancer development; however, the molecular mechanisms by which these cells escape conventional therapies remain elusive. In this study, TICs were isolated from ovarian cancer cells as tumor spheres with specific stem properties under TIC-selective conditions. Unlike non-TICs, TICs strongly express stem cell factor (SCF) and c-Kit. Blocking SCF-c-Kit by SCF neutralizing antibodies, c-Kit small interfering RNA (siRNA) or imatinib (Gleevec), a clinical drug that inhibits c-Kit signaling, significantly inhibited TIC proliferation. Although cisplatin and paclitaxel killed the non-TICs, they did not eliminate TICs. Importantly, the combination of cisplatin/paclitaxel with c-Kit siRNA or imatinib inhibited the growth of both non-TICs and TICs. Similar results were obtained when patient-derived TICs were used. The findings also indicate that tumor-predisposing microenvironment, such as hypoxia, may promote ovarian TICs through upregulating c-Kit expression. Furthermore, I have showed that c-Kit expression induced activation of Phosphatidylinositol 3-kinases (PI3K)/Akt, -catenin, and ATP-binding cassette G2, which could be reversed by treatment with the PI3K/Akt inhibitor or -catenin siRNA. I further studied potential gene expression in TICs using cDNA and microRNA (miRNA) microarrays. The result from these microarrays provided a general profile in gene expression of TICs compared with the bulk tumor cells. In particular, let-7a, b, and c were shown to be downregulated in TICs compared to bulk tumor cells, suggesting that their loss may contribute to ovarian cancer development. Together, this study reveals a previously undescribed therapeutic effect of SCF-c-Kit signaling blockade to prevent ovarian cancer progression by eliminating TICs and the altered genes or miRNAs may represent possible molecular targets.published_or_final_version
Biological Sciences
Master
Master of Philosophy
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Zhang, Luduo, and 张露朵. "Splice variant profiling in relation to tamoxifen resistance in breastcancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45526424.
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Po???uha, Sela Tu???ipulotu Chemical Sciences & Engineering Faculty of Engineering UNSW. "Role of Actin and its regulating proteins in drug response." Awarded by:University of New South Wales. School of Chemical Sciences and Engineering, 2006. http://handle.unsw.edu.au/1959.4/28286.
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Antimicrotubule drugs are used in the treatment of childhood neuroblastoma and acute lymphoblastic leukaemia (ALL). Resistance to these agents can be a major clinical problem and mechanisms mediating resistance are not fully understood. Previous studies have reported an association between the actin cytoskeleton and resistance to antimicrotubule drugs. Thus, the aim of this study was to investigate the role of the actin regulating proteins, LIM kinases (LIMK1 and LIMK2) in drug resistance. In addition, the role of ?? actin, a major actin isoform, in drug resistance was also examined. Chapter 1 reviewed the known mechanisms of antimicrotubule drug resistance and the interaction between the microtubules and actin cytoskeleton. The methodologies used in this study are described in chapter 2. LIMKs are known to regulate the actin cytoskeleton via phosphorylation of cofilin. Real Time RT PCR and western blotting was used in chapter 3 and showed that expression of LIMKs and their downstream target cofilin was altered in antimicrotubule resistant neuroblastoma and leukaemia cells. Moreover, altered LIMK expression was detected in in vivo derived vincristine resistant ALL xenografts and ALL clinical samples, further demonstrating that alterations in LIMKs and cofilin are associated with antimicrotubule drug resistance. Importantly, in chapter 4, gene silencing and drug treated clonogenic assays were performed to elucidate the functional role of LIMK1 and LIMK2 in drug response. Silencing of LIMK1 and/or LIMK2 increased sensitivity of neuroblastoma cells to microtubule targeting drugs and DNA damaging agents, suggesting that LIMKs may be useful targets to improve the efficacy of anticancer drugs. ??-Actin has been associated with drug resistance and chapter 5 used gene silencing and drug treated clonogenic assays to show that decreased ?? actin expression conferred resistance to anitmicrotubule drugs but not to DNA damaging agents. Microscopy and tubulin polymerisation assays showed that reduced ??-actin protects microtubules from paclitaxel induced polymerisation. This data supports a functional role for ?? actin in antimicrotubule drug action. In conclusion, this study showed that LIMKs and ?? actin mediate the action of antimicrotubule drugs and other anticancer agents, demonstrating that the actin cytoskeleton may serve as a useful drug target to improve the efficacy of anticancer drugs.
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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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Chan, Kin Tak. "Investigations of p53 mutations and effects on drug resistance /." View abstract or full-text, 2003. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202003%20CHAN.
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Prakash, Anand. "Characterization of synergistic effect of iododeoxyuridine and clofarabine in cisplatin-resistant ovarian cancer cells." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2009m/prakash.pdf.
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Wong, Ka Yeung Mark. "Drug clearance mechanisms and chemotherapy response." Thesis, The University of Sydney, 2007. https://hdl.handle.net/2123/28094.
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Cytotoxic chemotherapeutic agents have a major role in the treatment of cancers. However, many cytotoxic agents have a narrow therapeutic window with best treatment response achieved only within a small range of drug concentrations.
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Hamel, Sophie. "DARPP-32 expression in acquired resistance of breast cancer cells to trastuzumab." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112631.
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Amplification of the receptor tyrosine kinase ErbB-2 has been linked to the proliferation of breast cancer cells.1,2 Trastuzumab targets the extracellular domain of ErbB-2, leading to growth inhibition of approximately 15% of the breast cancers with genomic amplification of the ERBB2 gene.3 Clinical studies have demonstrated its efficacy in both early4 and metastatic breast cancers. 5,6 However, many tumors with ERBB2 amplification are not responsive to treatment.7 Moreover, the ones that initially respond, eventually progress and acquire drug resistance.8 An in vitro model for this acquired resistance was established by Chan & al.9 The breast cancer cell line, BT474, containing amplified ERBB2, was grown in the presence of trastuzumab for several months until subclones outgrew. Gene expression profiling was performed on these clones to determine differentially expressed genes between the parental and resistant cells. DARPP-32 (Dopamine and cAMP regulated phosphoprotein of 32kDa) was, by far, the most overexpressed transcript. DARPP-32 is coamplified with ERBB2 on the same amplicon of chromosome 17.10 This protein has been mostly described in neurobiology, but DARPP-32 overexpression was recently reported in gastrointestinal, esophageal, prostate and breast cancer.11 Therefore, we suggest that overexpression of DARPP-32 can cause acquired resistance of breast cancer cells to trastuzumab. The in vitro knockout of DARPP-32, using stable shRNA transfection, abolishes the resistance to trastuzumab in the clones, while overexpression of DARPP-32 in the parental cells results in de novo resistance. Overall, our results suggest that DARPP-32 may be a potential therapeutic target in breast cancer patients who develop acquired trastuzumab resistance.
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Lu, Shan. "Characterization, Epigenetic Drug Effect, and Gene Delivery to Breast Cancer Cells." University of Akron / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=akron1447718189.
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Kim, Gloria J. "Cancer nanotechnology engineering multifunctional nanostructures for targeting tumor cells and vasculatures /." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/22610.
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Thesis (Ph. D.)--Biomedical Engineering, Georgia Institute of Technology, 2007.Committee Chair: Nie, Shuming; Committee Member: Lyon, L. Andrew; Committee Member: McIntire, Larry V.; Committee Member: Murthy, Niren; Committee Member: Prausnitz, Mark R.
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Ajabnoor, Ghada. "Mechanism of cell death in drug resistant human breast cancer cells." Thesis, University of Surrey, 2010. http://epubs.surrey.ac.uk/842867/.
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Anticancer drug resistance occurs as a result of altered response to cytotoxic insult, via inhibition or inactivation of apoptosis (programmed cell death type I, PCDI), which plays a major role in tumour development and progression. An alternative form of cell death - non-apoptotic, or autophagic cell death (PCD II) has recently emerged as a factor contributing to the cytotoxic response of cancer cells. We studied in vitro cell death in a drug resistant model MCF-7 human breast cancer cells with acquired resistance (c. 10- 20 fold) to paclitaxel, termed MCF-7TaxR. It has been reported that the absence of caspase-3 in parental MCF-7 cells (due to chromosome deletion) may explain why they recruit apoptotic and autophagic cell death following cytotoxic insult. We investigated the induction of apoptosis response to staurosporine and Z-VAD (pan-caspase inhibitor) using the Annexin V-FITC/PI assay and studied the effect of anti-Fas on MCF-7TaxR. Results demonstrated the lack of apoptosis induction in paclitaxel resistant breast cancer cells. The oligo GEAiTayRTM human apoptosis microarray and qPCR analysis confirmed the absence of caspase-7 and caspase-9 genes and many other apoptosis genes in MCF-7TaxR cells and their presence in MCF-7 cells. Western blot analysis also confirmed these results. Therefore, we investigated the presence of autophagic cell death in our MCF-7TaxR model. Flow cytometry using Acridine Orange assay, Beclin 1 and LC-3 protein detection, confocal microscopy and detection of Akt/mTOR expression. Data showed evidence of autophagic cell death in MCF-7TaxR cells in the absence of an apoptotic response. Collectively, these findings indicate the lack of involvement of caspase mediated cell death in a paclitaxel drug-resistant cancer cell line MCF-7TaxR, and presence of autophagic cell death as an alternative cell death mechanism.
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Liu-Chen, Xinyue. "Novel strategies to treat human cancer cells : resistant to thymidylates synthase inhibitors /." Access full-text from WCMC:, 1999. http://proquest.umi.com/pqdweb?did=1432807601&sid=7&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Eyre, Rachel. "Determining the genes responsible for drug resistance in ovarian and breast cancer stem cells." Thesis, University of Newcastle Upon Tyne, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.576535.
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The majority of deaths in ovarian and breast cancer are caused by recurrent metastatic disease which is usually multidrug resistant. This progression has been hypothesised to be due in part to the presence of cancer stem cells, a subset of cells which are capable of self renewal and are able to survive chemotherapy and migrate to distant sites. Side population (SP) cells, identified by the efflux of the DNA binding dye Hoechst 33342 through ABC transporters, are a known adult stem cell group and have been suggested as a cancer stem cell in various cancers. The aims of this study were (i) to determine the presence and prevalence of SP cells in ovarian and breast cancer cell lines and clinical samples, and (ii) to ascertain their role both as cancer stem cells and in cancer drug resistance through ABC transporter identification and specific transporter knockdown. SP cells were identified in both ovarian and breast cancer cell lines and clinical samples. These SP cells expressed known stem cell genes and exhibited stem cell characteristics. SP cells in both ovarian and breast cancer cell lines were more drug resistant than non- SP (NSP, bulk tumour cells), and furthermore this drug resistance was shown to be due to expression of different ABC transporters in different tissue specific cancers. ABCG2 was found to be the predominate transporter expressed in breast cancer cell line derived SP populations, however silencing ABCG2 in MCF-7 breast cancer cell SP did not either completely inhibit SP presence or increase cell sensitivity to chemotherapy. In contrast ABCB1 was the predominant transporter expressed in ovarian cancer cell line (IGROV1 and HeyA8MDR) derived SP cells and silencing this transporter both fully inhibited SP cells and significantly increased SP cell death following treatment with paclitaxel. In clinical samples, the presence of SP cells in fine needle aspirates from breast cancer patients correlated to oestrogen receptor negative disease and the triple negative phenotype (ER-,PR-,HER2-), a marker of poor patient prognosis. This study has provided evidence of a role for SP cells in both breast and ovarian cancer. SP cells have a possible prognostic role in breast cancer, and ABCB1 should be considered as a therapeutic target in ovarian cancer.
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Odii, Benedict Onyekachi. "Roles of transglutaminase 2 in development of drug resistance and metastasis by cancer cells." Thesis, Anglia Ruskin University, 2014. http://arro.anglia.ac.uk/550361/.
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Wu, Fangting. "The Role Of Ubc9 In Drug Resistance And Its Expression Regulation In Cancer Cells." Available to subscribers only, 2009. http://proquest.umi.com/pqdweb?did=1879689211&sid=15&Fmt=2&clientId=1509&RQT=309&VName=PQD.
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Thesis (Ph. D.)--Southern Illinois University Carbondale, 2009."Department of Medical Microbiology Immunology and Cell Biology." Keywords: Cancer cells, Drug resistance, Regulation, Ubc9, Sumoylation. Includes bibliographical references (p. 74-96). Also available online.
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Rajabi, Fatemeh. "Role of the xenoreceptor PXR (NR1I2) in colon cancer stem cells drug resistance and tumor relapse." Thesis, Montpellier, 2015. http://www.theses.fr/2015MONTT027.
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La récidive tumorale est l'un des principaux obstacles à surmonter à l'avenir pour améliorer la survie globale des patients atteints de cancer du côlon (CCR). Les échecs thérapeutiques observés chez les patients sont compatibles avec une accumulation de cellules souches cancéreuses (CSCs) résistantes aux médicaments. Dans cette étude, nous démontrons que le récepteur nucléaire PXR (NR1I2) agit comme un régulateur important de la chimiorésistance des CSCs coliques et de leur capacité à initier la rechute tumorale après traitement. Nous avons d'abord montré que l'expression de PXR augmente avec celle de certains marqueurs des CSCs dans des cellules cancéreuses de patients CCR traitées par chimiothérapies. Nous avons constaté que PXR est préférentiellement exprimé dans les CSCs coliques et qu'il contribue à l'enrichissement des CSCs après chimiothérapies in vitro et in vivo. Par des approches de transcriptomiques, nous avons observé qu'au sein des CSCs coliques, PXR contrôle l'expression d'un large réseau de gènes marqueurs des CSCs coliques, ainsi que des gènes impliqués dans la résistance aux médicaments ou à l'apoptose, ou impliqués dans la dissémination métastatique. Enfin, l'inhibition de PXR par interférence à ARN diminue la survie et auto-renouvèlement des cellules souches cancéreuses du côlon in vitro, ainsi que leur capacité à résister à la chimiothérapie après xénogreffes, conduisant à des retards importants de rechute tumorale après traitements par chimiothérapies in vivo. Cette étude suggère fortement que l'inhibition ciblée de PXR peut représenter une stratégie de traitement néo-adjuvant afin de diminuer la résistance aux médicaments et la récidive des patients CCR via la sensibilisation des cellules souches cancéreuses aux chimiothérapies classiquesTumor recurrence is one of the major obstacles to overcome in the future to improve overall survival of patients with colon cancer. High rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). Here, we demonstrate that the nuclear receptor PXR (NR1I2) acts as a key regulator of colon CSC chemoresistance and of their ability to generate post-treatment tumor relapse. We first determined that the enrichment of PXR paralleled that of CSC markers upon treatment of colon cancer cells with standard of care chemotherapy. We found that PXR was highly expressed in colorectal cancer cells displaying CSC markers and function and that it was instrumental for the emergence of CSCs following chemotherapy in vitro and in vivo. mRNA profiling experiments in colon CSCs indicated that PXR transcriptionally controls a large network of genes including markers of stemness, genes involved in resistance to drug/apoptosis or migration/invasion. Finally, PXR down-regulation altered the survival and self-renewal of colon CSCs in vitro and hampered their capacity to resist chemotherapy in vivo, leading to significant delays of post-chemotherapy tumor relapse. This study strongly suggests that targeting PXR may represent a novel treatment strategy to prevent drug resistance and recurrence through the sensitization of CSCs to standard chemotherapy. Taken together, our data strongly suggest that PXR plays an instrumental role in the so-called "intrinsic" pan-resistance of CSCs against therapy
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Ardehali, M. Behfar M. "Degradation of human vault RNA1 by RNA interference and multidrug resistance in GLC4/REV, a small-cell lung cancer cell line." Virtual Press, 2003. http://liblink.bsu.edu/uhtbin/catkey/1265086.
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Ferguson, Paul R. "The role of thymidylate synthase in modulating sensitivity to chemotherapeutic agents." Thesis, Queen's University Belfast, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326399.
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Sun, Jisan. "Potential role of Oct3/4 in chemo-resistant cancer stem like cells /." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38657405.
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Sun, Jisan, and 孫紀三. "Potential role of Oct3/4 in chemo-resistant cancer stem like cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B45011461.
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Maung, Zor T. "A study of in vitro drug resistance ofleukaemic cells from patients with acute lymphoblastic leukaemia." Thesis, University of Newcastle Upon Tyne, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320828.
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Gan, Pei Pei Children's Cancer Institute Australia for Medical Research Faculty of Medicine UNSW. "Determining the role of β-tubulin isotypes in drug resistance and tumourigenesis in lung cancer cells." Publisher:University of New South Wales. Children's Cancer Institute Australia for Medical Research, 2009. http://handle.unsw.edu.au/1959.4/43357.
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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide and in its advanced stage, has a poor clinical outcome. Resistance to chemotherapeutic agents, either intrinsic or acquired, is the primary cause of treatment failure in NSCLC. Tubulin binding agents (TBAs), such as paclitaxel and vinorelbine are important components in the treatment of NSCLC. Upregulation of the neuronal specific class III β-tubulin (β-III-tubulin) is frequently found in drug resistant cancer cell lines and human tumours, lending support that βIII-tubulin might play a role in the development of drug resistance in cancer cells. However, to date, compelling evidence supporting its direct role in drug resistance and response has been lacking. To address its role in NSCLC, RNA interference (RNAi) was employed to knock down βIII-tubulin expression in two drug naive NSCLC cell lines, Calu-6 and H460. Specific knockdown of βIII-tubulin resulted in increased sensitivity to TBAs and DNA damaging agents, two classes of agents that are commonly used in the treatment of NSCLC. Increased sensitivity to TBAs and DNA damaging agents in the βIII-tubulin knockdown cells was due to an increased propensity of the cells to undergo apoptosis, suggesting that this tubulin isotype may be a cellular survival factor. Interestingly, specific knockdown of βII- or βIVb-tubulin hypersensitised the cells to Vinca alkaloids but not taxanes, demonstrating that each isotype is unique in terms of drug-target interactions. Moreover, the β-tubulin isotype composition of a cell can influence response, and therefore resistance to TBAs. To determine whether βIII-tubulin differentially regulates microtubule behaviour and influences cell proliferation via an effect on microtubule dynamics, siRNAs were used to knockdown βIII-tubulin expression in H460 cells stably expressing GFP-βI-tubulin and the dynamic instability behaviour of individual microtubules was measured by time-lapse microscopy. In the absence of drug, silencing of βIII tubulin alone did not significantly affect the dynamic instability of interphase microtubules. However, at the IC50 for proliferation of either paclitaxel or vincristine, the overall dynamicity was suppressed significantly in the βIII-tubulin silenced cells as compared to the control, indicating that βIII-tubulin knockdown induces paclitaxel or vincristine sensitivity by enhancing the ability of these agents to suppress microtubule dynamics. At a concentration of drug that represented the IC50 for mitotic arrest, for either paclitaxel or vincristine, increased apoptosis induction was found to play a dominant role in βIII-tubulin knockdown, further supporting a role for βIII-tubulin as a cellular survival factor. Collectively, when βIII-tubulin is overexpressed in tumours cells, it is highly likely to be promoting cellular survival and resistance to TBAs. In addition to its proposed role in drug resistance, high expression of βIII-tubulin in tumours of non-neuronal origin such as NSCLC, has been positively correlated with the degree of tumour aggressiveness. H460 cells are known to display substrate- independent growth in soft agar and tumourigenicity in nude mice and provided an ideal model to investigate the role of βIII-tubulin in tumourigenesis. To address the role of βIII-tubulin, H460 cells stably expressing βIII-tubulin shRNA were generated, validated and examined using both in vitro and in vivo methods of tumourigenesis. Colony formation of H460 cells stably expressing βIII-tubulin shRNA was dramatically reduced in soft agar and significantly delayed tumour growth and reduced tumour incidence of subcutaneous xenografted tumours in nude mice when compared to respective controls. These results provide new insights into the function of βIII-tubulin and suggest that βIII-tubulin may play an important role in tumour development and progression in lung cancer. In conclusion, β-tubulin isotype status can serve as a valuable molecular marker capable of distinguishing patients with differential sensitivity to TBAs. These results not only shed new light on the role of specific β-tubulin isotypes in the response to TBAs, but also the role of βIII-tubulin in the biology of cancer that will lead to new treatment strategies for NSCLC.
34
Moore, Sarah Margaret. "Phosphoinositide 3-kinase regulation of anchorage-independent growth and drug resistance in small cell lung cancer cells." Thesis, University of Edinburgh, 1999. http://hdl.handle.net/1842/21429.
Full textAbstract:
In this thesis it is shown that PI 3-kinase is constitutively activated in SCLC cell lines (H69, H345 and H510). Inhibition of PI 3-kinase activity using the selective inhibitors wortmannin and LY294002 markedly inhibits cell proliferation and stimulates apoptosis in liquid media. This inhibition of proliferation is shown to occur via both ribosomal protein s6 kinase (p70s6kinase) dependent and independent mechanisms. Furthermore, PI 3-kinase inhibition reduced basal SCLC cell growth in agarose semi-solid media which could not be rescued by the addition of neuropeptides. This is the first description of a constitutively activated PI 3-kinase in any human cancer. It is proposed that this constitutive activity plays an important role in promoting growth, anchorage-independence and tumorigenicity in SCLC, and may account for the non-adherent phenotype and highly metastatic nature of this cancer. Resistance to chemotherapy is a major problem in the treatment of SCLC. Adhesion to extracellular matrix (ECM) proteins can protect cells from undergoing detachment-induced apoptosis. SCLC cells in vivo are surrounded by a specialized micro-environment rich in ECM containing in part laminin, fibronectin and collagen IV. It is shown that SCLC cells adhere to the ECM proteins in vitro in a β1 integrin-dependent manner, enhancing tumourigenicity and conferring resistance to standard chemotherapeutic agents. This adhesion to ECM proteins increases SCLC cell growth and protects cells from the pro-apoptotic effects of the chemotherapy agents via a β1-integrin-dependent mechanism requiring tyrosine kinase activation. Thus ECM proteins in vivo may provide a signal resulting in resistance to chemotherapy. These findings may begin to proivde us with novel targets for the therapeutic intervention of SCLC.
35
Issa, Mark E., E. M. K. Wijeratne, A. A. L. Gunatilaka, and Muriel Cuendet. "Withanolide D Exhibits Similar Cytostatic Effect in Drug-Resistant and Drug-Sensitive Multiple Myeloma Cells." FRONTIERS MEDIA SA, 2017. http://hdl.handle.net/10150/625811.
Full textAbstract:
In spite of recent therapeutic advances, multiple myeloma (MM) remains a malignancy with very low curability. This has been partly attributed to the existence of a drug-resistant subpopulation known as cancer stem cells (CSCs). MM-CSCs are equipped with the necessary tools that render them highly resistant to virtually all conventional therapies. In this study, the growth inhibitory effects of withanolide D (WND), a steroidal lactone isolated from Withania somnifera, on drug-sensitive tumoral plasma cells and drug-resistant MM cells have been investigated. In MTT/XTT assays, WND exhibited similar cytostatic effects between drug-resistant and drug-sensitive cell lines in the nM range. WND also induced cell death and apoptosis in MM-CSCs and RPMI 8226 cells, as examined by the calcein/ethidium homodimer and annexin V/propidium iodide stainings, respectively. To determine whether P-glycoprotein (P-gp) efflux affected the cytostatic activity of WND, P-gp was inhibited with verapamil and results indicated that the WND cytostatic effect in MM-CSCs was independent of P-gp efflux. Furthermore, WND did not increase the accumulation of the fluorescent P-gp substrate rhodamine 123 in MM-CSCs, suggesting that WND may not inhibit P-gp at the tested relevant doses. Therefore, the WND-induced cytostatic effect may be independent of P-gp efflux. These findings warrant further investigation of WND in MM-CSC animal models.
36
Chow, Hoi-yee, and 鄒凱兒. "Applications of proteomics: identification ofgenes associated with anti-cancer drug resistance, liver developmentand regeneration." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B3876796X.
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Yang, Ruizhen. "Cell-type and stimulus-dependent activation of p53 pathway in response to cytotoxic chemotherapeutics." HKBU Institutional Repository, 2019. https://repository.hkbu.edu.hk/etd_oa/646.
Full textAbstract:
Studies of drug resistance mostly characterize genetic mutations, and we know much less about the phenotypic mechanisms of drug resistance, especially at a quantitative level. p53 is an important mediator that regulates the cellular response to chemotherapy, but even cancer cells with wild-type p53 exhibited variable drug sensitivity for unclear reasons. In this PhD thesis, I investigated the mechanistic basis underlying differential p53 pathway activation in response to two types of chemotherapeutics, i.e., etoposide (a DNA-damaging drug) and 5-fluorouracil (5-FU, an antimetabolites), which led to distinct cell fate outcome in drug sensitive vs. resistant cancer cells. Specifically, I uncovered a new resistance mechanism to etoposide through bimodal modulation of p53 activation dynamics and characterized a four-component regulatory module, involving ATM, p53, Mdm2 and Wip1, which generates bimodal p53 dynamics through coupled feed-forward and feedback loops. Moreover, I found that the inhibitory strength between ATM and Mdm2 determined the differential modular output between drug sensitive and resistant cancer cell lines, and that combinatorial inhibition of Mdm2 and Wip1 was an effective strategy to alter p53 dynamics in resistant cancer cells and sensitize their apoptotic response, pointing to p53 pulsing as a potentially druggable mechanism that mediates resistance to DNA damaging chemotherapy. As for response to 5-FU, preliminary results illustrated that 5-FU activated p53 and differential cell fate outcome via ribosomal stress, rather than DNA damage. Different from dose response to etoposide, 5-FU-induced p53 activity was not only regulated by p53 induction level but also p53 phosphorylation by kinases, such as DNA-PK. Overall, this thesis presented original results that elucidated phenotypic mechanism of chemoresistance and provide new angles towards developing more effective combinatorial anticancer therapy.
38
Picco, Noemi. "Tumour-stromal interactions in cancer progression and drug resistance." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:c05135ed-2334-4788-b623-262b5056a014.
Full textAbstract:
The typical response of cancer patients to treatment is only temporary, and is often followed by relapse. The failure of various therapeutic strategies is commonly attributed to the emergence of drug resistance. The response patterns for patients under such treatments indicate that complex dynamics regulate the response of the tumour to the therapy. The environment in which the tumour lives (the stroma) is known to be a modulator of multiple mechanisms that lead to drug resistance and seems to be a likely candidate for explaining some of this complexity. Understanding the role of stromal cells in the promotion of drug resistance is critical for the design of optimal treatment strategies, and for the development of novel therapies that selectively target both the tumour and the stroma. In this thesis we design two novel mathematical models that describe cancer growth within its environment and the evolution of drug resistance within spatially complex and temporally dynamic tumours. A compartment model captures clinically observed dynamics and allows direct comparison with experimental data, facilitating model parametrisation and the understanding of inter-tumour heterogeneity. An individual cell-based model highlights the key role of local interactions, determining heterogeneity at the tissue scale, that will eventually determine treatment outcome. A non-spatial approximation of this second model allows us to find analytic guidelines for the design of effective therapy. These tools allow the simulation of a range of treatment strategies (including combination of different drugs and variation of schedule) as well as the investigation of therapy response based on patient- or organ-specic parameters. The work developed in this dissertation is based on the paradigmatic biology of melanoma and non-small cell lung cancer. Its results are therefore applicable to a variety of cancer treatments that target similar processes, and whose therapeutic failure can be attributed to environment-mediated drug resistance.
39
Castilho, Antonia Genevieve. "Identification of liver tumour-initiating cells using a chemoresistantanimal model." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45165415.
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Man, Cheuk-him, and 文卓謙. "Mechanism of sorafenib resistance in FLT3-ITD⁺ acute myeloid leukemia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193461.
Full textAbstract:
Acute myeloid leukemia (AML) is a group of heterogeneous diseases characterized by an abnormal increase in myeloblasts in circulation and/or bone marrow. Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene occurs in about 30% of AML and is associated with an inferior prognosis. Tyrosine kinase domain (TKD) mutations occur in about 5% with uncertain prognostic significance. Intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) are the mainstays of treatment. However these approaches have reached a deadlock with a cure rate of 30-40%. Targeting FLT3 in AML with multi-tyrosine-kinase inhibitors has been evaluated in Phase II/III clinical trials. Despite an initial clearance of myeloblasts, the leukemia invariably progresses despite continuous treatment. The mechanisms of drug resistance and leukemia progression, hence the effective therapeutic strategies are currently unknown, limiting its clinical application.
These issues were addressed in the present study. In the first part, 13 patients with chemo-refractory or relapsed FLT3-ITD+ AML received sorafenib 200-400 mg twice daily of whom 12 patients achieved clearance or near clearance of bone marrow blasts after a median of 27 days (range 21-84 days). There was evidence of myeloid differentiation of the leukemia blasts at remission. Leukemia progression occurred in 9 patients after a median of 72 days (range 54-287 days) and in 4 out of 6 patients it was dominated by clones carrying double FLT3-ITD and -TKD mutations. Microarray studies comparing myeloblasts before sorafenib treatment (sorafenib naïve) and at subsequent progression (sorafenib resistant) demonstrated up-regulation of 64 genes including ALDH1A1, JAK3 and TESC whose functions were unknown in AML. Transplantation of sorafenib naïve and resistant myeloblasts into NOD/SCID mice recapitulated their clinical behavior when the animals were treated with sorafenib. Both ITD and TKD mutations at D835 were identified in leukemia initiating cells (LICs) from sorafenib naïve samples. These results suggested that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations.
In the second part, the gene encoding tescalcin (TESC), that was up-regulated at sorafenib resistance and was known to activate a sodium/hydrogen exchange (NHE1), was evaluated to examine its link with TKI resistance. TESC was highly expressed in FLT3-ITD+ AML cell lines MOLM-13 and MV4-11 and its knock-down by siRNA lowered intracellular pH and induced apoptosis. The results were recapitulated by treatment with a NHE1 inhibitor, 5-(N,N-Hexamethylene)amiloride (HMA). Induction of sorafenib resistance in MOLM-13 cell line (MOLM-13-RE) significantly increased its sensitivity to HMA. HMA treatment of MOLM-13 and MV4-11 as well as primary FLT3-ITD+ AML cells significantly reduced leukemia initiation in NOD/SCID mouse xenotransplantation. Normal CD34+ cells engraftment was not affected. HMA treatment significantly enhanced suppression of FLT3 signaling by sorafenib even in sorafenib resistant cell lines. These observations provided novel information about the pathogenetic role of TESC-NHE1-pHi in sorafenib resistance in AML.
In conclusion, the information derived from the present study has provided mechanistic insights to the emergence of drug resistance during sorafenib treatment and important guide for future therapeutic strategies targeting FLT3-ITD+ AML.published_or_final_version
Medicine
Doctoral
Doctor of Philosophy
41
Williams, Jacob Brian. "Nanoemulsions Within Liposomes for Cytosolic Drug Delivery to Multidrug-Resistant Cancer Cells." BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/6211.
Full textAbstract:
Cancer cells that survive chemotherapy treatment often develop resistance to the administered chemotherapeutics, as well as to many other types of drugs, because the cancer cells increase their production of efflux pumps in the cell. This undesired phenomenon of resistance to cancer drugs is known as multidrug resistance. This work uses a novel drug carrier, called an eLiposome, to achieve cytosolic drug delivery to kill multidrug-resistant cancer cells. An eLiposome consists of a perfluoropentane (PFC5) emulsion droplet inside of a liposome. Folate attached to the eLiposome facilitates uptake into the cell. The PFC5 droplet is metastable at body temperature, but will rupture the liposome as the droplet expands during vaporization, and will release any drugs encapsulated inside of the liposome directly to the cell cytosol. Laser and ultrasound were examined as triggers to initiate the vaporization of the PFC5 droplet and actuate the release of doxorubicin (Dox) from folated eLiposomes containing Dox (feLD). Gold nanorods (GNRs) were synthesized and transferred to PFC5 droplets. Although GNRs are efficient at converting irradiated laser light to heat, no vaporization of the PFC5 droplets was observed when irradiated with laser light. Further investigation into the energy required for vaporization of PFC5 droplets revealed that there are currently no portable and wearable lasers available to provide enough energy to vaporize PFC5 droplets. Two seconds of ultrasound can release 78% of encapsulated Dox from feLD. Dox-sensitive KB-3-1 cells and Dox-resistant KB-V1 cells treated with feLD (without ultrasound) had cell viabilities of 33% and 60%, respectively. Ultrasound had negligible additional effect on the cell viability of KB-3-1 and KB-V1 cells treated with feLD (33% and 53%, respectively). We hypothesized that the Dox fiber formed during the loading of Dox into the eLiposome is a site for heterogeneous nucleation once the feLD is endocytosed by the cell, and vaporization and drug release occurs with or without ultrasound. Blocking the efflux pumps with verapamil decreases the rate at which Dox is exported from multidrug-resistant cells. When verapamil is co-delivered with feLD, the cell viability of KB-3-1 and KB-V1 cells decreases to 29% and 25%, respectively; thereby reversing the multidrug resistance possessed by KB-V1 cells. The delivery of doxorubicin inside of folated eLiposomes with an efflux pump blocker is a novel way to kill multidrug-resistant cancer cells as effectively as non-resistant cancer cells independent of lasers or ultrasound.
42
Bell, Susan Elizabeth. "Mechanisms underlying the preferential killing of human multidrug resistant KB carcinoma cells by 2-deoxy-d-glucose." Thesis, University of York, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265563.
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Lo, Jessica, and 盧姵岐. "Functional characterization and therapeutic implication of CD47 in sorafenib resistance in hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208547.
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McEwan, David George. "Cyclic AMP modulation and its effects on chemo-resistant colon cancer cell proliferation and survival." Connect to e-thesis, 2007. http://theses.gla.ac.uk/81/.
Full textAbstract:
Thesis (Ph.D.) - University of Glasgow, 2007.Thesis submitted in part fulfilment of the Ph.D. to The Beatson Institute for Cancer Research, Faculty of Medicine, University of Glasgow, 2007. Includes bibliographical references. Print version also available.
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Iliopoulos, Dimitrios. "The role of the WWOX tumor suppressor in breast and lung cancer." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1155142398.
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Lau, Lai-yee, and 劉麗儀. "Identification of microRNAs associated with tamoxifen resistance in breast cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47235792.
Full textAbstract:
Tamoxifen is the most widely used endocrine therapy for both early and advanced estrogen receptor (ER) positive breast cancer patients. About half of the patients that initially respond to the antiestrogen become estrogen-independent and ultimately develop resistance to the treatment. The precise molecular mechanisms of tamoxifen resistance remain poorly understood. Dysregulation of microRNAs (miRNAs) has been frequently reported in breast cancer and linked to cancer development, progression and therapeutic response.
To gain a more comprehensive picture of the miRNA regulatory network for modulating tamoxifen responsiveness, we examined global expression profiles of more than 600 miRNAs in a matched pair of tamoxifen-sensitive ZR75 and tamoxifen-resistant AK47 breast cancer cell lines using TaqMan Low Density Array (Applied Biosystems). Under 4-hydroxytamoxifen treatment, 102 miRNAs displayed differential responses between the sensitive cells and the resistant cells. At basal levels, upregulation of 32 miRNAs and downregulation of 75 miRNAs were observed in the resistant cells as compared to the sensitive cells. Among the 9 miRNAs of significant differential expression selected for validation, expression profiles of the 7 miRNAs could be reproduced. Of these, 4-hydroxytamoxifen treatment greatly increased miR-449a/b expression in sensitive ZR75 cells, whereas miR-449a/b expression was significantly reduced in resistant AK47 cells at basal levels, which was further confirmed in a panel of tamoxifen-resistant breast cancer cell lines. Such downregulation of miR-449a/b in the resistant cells was partially attributed to DNA methylation-mediated repression of miR-449a/b. Notably, miR-449a/b expression exhibited a significant positive correlation with ER-α status (miR-449a: P=0.006, miR-449b: P=0.013) and progesterone receptor (PR) status (miR-449a: P=0.010, miR-449b: P=0.021), and a prominent inverse association with tumor grade in 61 breast cancer tissues (miR-449a: P=0.001; miR-449b: P=0.009). Also, breast cancer patients with high miR-449a/b expression tended to have increased disease-free survival (miR-449a: P=0.019; miR-449b: P=0.117).
To further support the tumor suppressor function of miR-449, stable miR-449b overexpression in the resistant cells reduced cell proliferation. More intriguingly, restoring miR-449b expression increased sensitivity to 4-hydroxytamoxifen-induced apoptosis via suppression of AKT activity without restoring ER-α expression. In contrast, miR-449a/b knockdown reduced ER-α and PR expression, but enhanced phosphorylation of AKT, extracellular signal-regulated kinase- 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and also ER-α at serine 167 and serine 118 residues. Furthermore, we demonstrated c-Myc is a target gene of miR-449 as confirmed by bioinformatics and experimental analyses. Computational algorithms predicted a highly conserved miR-449a/b binding site within C-MYC 3’untranslated region (3’UTR). Compared to the parental sensitive cells, c-Myc was overexpressed in the resistant cells. Forced expression of miR-449b suppressed c-Myc protein level. To further support the notion that c-Myc is a direct target of miR-449, interactions between miR-449b and C-MYC 3’UTR were confirmed by co-expression of miR-449b and c-Myc expression constructs and luciferase reporter assay.
Taken together, our data strongly suggest the critical role of miR-449 in modulating altering response to tamoxifen via targeting c-Myc. Suppression of miR-449 repressed genomic ER action and concomitantly activated non-genomic ER pathways. These findings may provide insights to improve breast cancer management and open a wide avenue for therapeutic interventions for overcoming tamoxifen resistance.published_or_final_version
Pathology
Doctoral
Doctor of Philosophy
47
Lee, Derek, and 李揚俊. "MicroRNA-210 and endoplasmic reticulum chaperones in the regulation of chemoresistance in glioma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206606.
Full textAbstract:
Gliomas are the commonest type of primary malignant brain tumours of the central nervous system (CNS). The highly aggressive and infiltrative characteristics of gliomas render them one of the most lethal cancers. Amongst all, the most malignant form of glioma is glioblastoma multiforme (GBM), a World Health Organization (WHO) grade IV astrocytoma. Despite well-developed multimodal treatment including surgery, radiotherapy, and chemotherapy, the prognosis of GBM patients remains poor with median survival of just over one year. This high mortality rate is commonly the result of relentless tumour recurrence secondary to the tumour’s intrinsic resistance towards its standard chemotherapeutic agent temozolomide (TMZ).
Prolyl 4-hydroxylase, beta subunit (P4HB) is an endoplasmic reticulum stress response (ERSR) chaperone protein that was previously found to be overexpressed in the chemoresistant glioma cell lines D54-MG and U87-MG. Differential expressions of numerous microRNAs (miRNAs) were also found between chemosensitive and chemoresistant glioma cell lines. As such, we surmised that the dysregulation of a P4HB-regulating miRNA may contribute to P4HB upregulation and therefore chemoresistance in glioma. MiR-210, a commonly dysregulated miRNA in various cancers, is one of the most highly downregulated miRNAs in chemoresistant glioma cells (compared to chemosensitive glioma cells), and, based on bioinformatics findings, may also regulate P4HB expression. MiR-210 was therefore selected for further investigations regarding its potential roles in glioma chemoresistance.
The regulatory relationship between P4HB and miR-210 was subjected for verifications. With the use of quantitative real-time polymerase chain reaction (qPCR) and western blotting, the intrinsic expressions of P4HB and miR-210 were studied. The upregulation of P4HB in D54 and U87 chemoresistant glioma (compared to the parental) cell lines were found to correlate reciprocally with the downregulation of miR-210 in the same chemoresistant glioma cells.
To delineate the potential regulatory role of miR-210, a gain of function approach was adopted. Transfection of a miR-210 mimic was performed into the D54 and U87 parental chemosensitive (D54-S and U87-S) and chemoresistant (D54-R and U87-R) cells, along with a negative control. The transfection efficiency of miR-210 as well as the subsequent P4HB expressions was verified. It was found that P4HB expression was downregulated as a result of miR-210 upregulation both at the mRNA and protein levels in glioma cells. Furthermore, the effects of miR-210 overexpression on chemoresistance in the glioma cells were tested by performing cell proliferation assay. Decrease in the half maximal inhibitory concentration (IC50) of TMZ were found in all cell lines overexpressing miR-210, suggesting that miR-210 upregulation may lead to P4HB inhibition, which would at least partially mediate an alleviation of glioma cells’ resistance towards its chemotherapeutic agent TMZ.
In summary, miR-210 is downregulated in chemoresistant glioma cells in vitro. It plays a potential role in regulating P4HB expression, hence chemoresistance in GBM cells. Future investigations may focus on its mechanism of action and potentiality for therapeutic intervention.published_or_final_version
Surgery
Master
Master of Medical Sciences
48
Zhuang, Tin-fong, and 莊天放. "Adducin 3 and temozolomide resistance in glioblastoma multiforme." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48335095.
Full textAbstract:
Glioblastoma multiforme (GBM), a grade IV malignant astrocytic tumor according to WHO classification, is one of the most common and malignant brain tumor. Temozolomide (TMZ) is the current standard treatment for GBM. Nevertheless, resistance to chemotherapy in GBM is common and therefore a major obstacle to successful treatment. Adducin 3 (ADD3), a cytoskeletal protein, has been found to be associated with chemoresistance in osteosarcoma, but its potential role in glioblastoma is unclear. A TMZ-resistant model was established by chronically exposing the glioma cells (D54 cell line) to an increasing dose of TMZ. A resistant subclone (D54-R) was successfully generated. ADD3 expression level was found to be upregulated in the D54-R when compared to the parental D54 cells (D54-C).
CD133 is a putative cancer stem cell marker. Its expression level was found also to be higher in D54-R when compared to D54-C cells. Among the D54-R cells, a subgroup of cells was found to express ADD3 intensely. The proportion of these spherical cells was higher in D54-R than D54-C. Moreover, these cells were spherical in morphology and expressed putative cancer stem cell markers: CD133, NANOG and OCT-3/-4. Therefore, ADD3 is associated with cancer stem cells in human glioma. The upregulation of ADD3 expression is associated with TMZ-resistance in GBM.published_or_final_version
Surgery
Master
Master of Research in Medicine
49
Wong, Wing-sum Winnie, and 王詠心. "Role of caveolin-1 in multidurg resistance in hepatocellularcarcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46632001.
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Lai, King-yin, and 賴景然. "The identification of 14-3-3 [sigma] as a contributor to cisplatin resistance in esophageal squamous cell carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208627.
Full textAbstract:
Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in Asia. Cisplatin is commonly used as an agent for treating ESCC patients undergoing chemotherapy. However establishment of resistance over the course of treatment diminishes the clinical usefulness and is one reason explaining poor prognosis of ESCC patients. In order to gain insights into the mechanism of cisplatin resistance in ESCC, HPLC/nESI-MS/MS proteomic profiling was employed to examine the global protein alterations of cisplatin-resistant ESCC cell line HKESC2/CDDP comparing with its parental cisplatin-sensitive cell line HKESC2. Stable over-expression and knocked-down cell lines were established for pathway analysis and functional studies. Seventeen proteins were identified with more than 2-fold difference in expression levels. These proteins are involved in endoplasmic reticulum stress response, metabolic processes, DNA replication and repair, nucleotide binding and cell cycle control, while some of them are components of cytoskeletal proteins. Among them, 14-3-3σ was one of the most significantly upregulated proteins found in HKESC2/CDDP cells and its differential expression levels were validated using western blotting and real-time quantitative polymerase chain reaction. Pathway analysis revealed that ectopic overexpression of 14-3-3σ caused a general upregulation in DNA repairing genes. Furthermore, functional validation showed that elevated 14-3-3σ expression contributed considerably to the observed cisplatin resistance in HKESC2/CDDP cells. While knocking down 14-3-3σ expression reversed the above situations in SLMT1 cells. I conclude that up-regulation in 14-3-3σ, together with DNA repairing genes, contributes to the establishment of cisplatin resistance in HKESC2/CDDP cells. Knocking down 14-3-3σ expression sensitized ESCC cells to cisplatin treatment, and hence, opens a therapeutic opportunity for ESCC cisplatin resistance.published_or_final_version
Surgery
Doctoral
Doctor of Philosophy