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Pharmacological modulation and manipulation of cancer drug resistance

Devery, Aoife (2010) Pharmacological modulation and manipulation of cancer drug resistance. PhD thesis, Dublin City University.

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Abstract

The aim of this project was to investigate pharmacological methods of overcoming resistance in cancer. Novel compounds, targeted therapies and non-steroidal anti-inflammatory drugs (NSAIDs) were examined for their potential to modulate and manipulate specific forms of drug resistance. Sixty one novel compounds were tested in combination with chemotherapeutic drugs in proliferation assays for their ability to overcome MRP1 and P-gp-mediated drug resistance. Two compounds were successful P-gp modulators in the DLKP-A cell line; the ditrifluoroacetyl resveratrol derivative, RBM15, and the macrocycle derivative, KG104. A panel of nine therapeutic agents were evaluated for their potential to down-regulate multidrug resistant protein expression and thus, overcome P-gp, MRP1 or BCRP-mediated drug resistance, at and below pharmacologically-relevant concentrations. Two of these agents (indomethacin and 17-AAG) partially down-regulated the expression of P-gp in the A549-Taxol cell line but did not overcome P-gp-mediated resistance when combined with docetaxel simultaneously or in pre-treated proliferation assays. Three agents (lapatinib, sulindac sulphide and 17-AAG) reduced the expression of MRP1 in the A549 cell line. Only sulindac sulphide overcame MRP1-mediated resistance in the combination proliferations assays; however, this was due to the inhibitory mechanism of sulindac sulphide and not due to the down-regulation of the MRP1 protein. Five agents (17-AAG, lapatinib, indomethacin, elacridar and gefitinib) down-regulated the expression of BCRP in the DLKP-SQ/mitox cell line. Lapatinib, gefitinib, elacridar and 17-AAG overcame BCRP-mediated resistance in both the combination and pre-treatment proliferation assays. The data indicates that the amount of down-regulation resulting from treatment with these drugs was insufficient to overcome drug resistance. Up-regulation of the three MDR transporter proteins was observed with a variety of agents tested. This suggests that, long-term treatment with such agents could lead to the development and amplification of multidrug resistance, and therefore, reduce the effectiveness of substrate chemotherapies in patients. Targeted therapies, including tyrosine kinase inhibitors (TKIs, such as lapatinib), are the latest significant development in the treatment of cancer. Lapatinib sensitised HER2-expressing cell lines to chemotherapeutic agents in the presence or absence of EGFR expression. This agent was also found to be a more active sensitiser in P-gp-expressing cell lines, while erlotinib was more active in BCRP-expressing cell lines. Gefitinib was the least active of three TKIs at modulating P-gp, MRP1 or BCRP. Following a 48 hours treatment, lapatinib up-regulated the expression and function of COX-2. It also stimulated COX-2 activity directly. This lapatinib-mediated COX-2 induction was independent of its TKI action on EGFR, and HER2 and could have serious therapeutic effects as COX-2 is known to increase cell growth, inhibit apoptosis, and enhance metastasis and angiogenesis. A COX-2-specific inhibitor, celecoxib, overcame P-gp, MRP1 and BCRP-mediated resistance. At pharmacologically relevant concentrations, celecoxib significantly overcame MRP1 and BCRP-mediated resistance. And to a much lesser extent celecoxib overcame P-gp mediated resistance above pharmacologically relevant concentrations. The combination of lapatinib with celecoxib could be of therapeutic benefit, as the combination of these agents could collectively inhibit COX-2, P-gp, MRP1, BCRP, HER2 and EGFR activity in tumours expressing multiple oncoproteins resistant pathways and enhanced signalling pathways. It is hoped that a novel treatment regimens, using these agents and TKI drugs with traditional chemotherapeutic agents, could improve current treatment strategies resulting in increased survival rates and decreased mortality.

Item Type:Thesis (PhD)
Date of Award:March 2010
Refereed:No
Supervisor(s):O'Connor, Robert and Clynes, Martin
Uncontrolled Keywords:cancer drug resistance; MDR; MRP; P-gp; celecoxib; toxicity testing;
Subjects:Medical Sciences > Pharmacology
Biological Sciences > Cell biology
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Biotechnology
Research Initiatives and Centres > National Institute for Cellular Biotechnology (NICB)
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
ID Code:15076
Deposited On:29 Mar 2010 15:59 by Robert O'Connor (Nursing). Last Modified 29 Mar 2010 16:03

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