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Drug sensitivity profiles in neuroblastoma cells with acquired resistance to stabilising tubulin binding agents

Kajewole, Deborah Ifeoluwa (2014) Drug sensitivity profiles in neuroblastoma cells with acquired resistance to stabilising tubulin binding agents. Master of Science by Research (MScRes) thesis, University of Kent,. (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided)

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Abstract

Tubulin-binding agents either inhibit microtubule formation (destabilising agents) or degradation (stabilising agents) thereby interfering with the dynamics required for microtubule functions resulting in cell cycle disruption and cell death. In this project, acquired resistance of neuroblastoma cell lines to tubulin-binding agents was studied. We investigated the resistance profiles of 10 clonal sub-lines of the docetaxel-resistant neuroblastoma cell line, UKF-NB-3rDOCE10 and 4 epothilone B-resistant UKF-NB-3 sub-lines that had been established in independent experiments against the tubulin-binding agents: combretastatin A4, 2-methoxyestradiol (destabilising agents, target the colchicine domain), vincristine, vinblastine (destabilising agents, target the vinca-domain), docetaxel, and epothilone B (stabilising agents, bind at the taxoid domain). Remarkable differences were detected in the resistance profiles of the UKF-NB-3rDOCE10 sub-clones and the epothilone B-resistant UKF-NB-3 sub-lines. Further, we started to establish a protocol for the standardised adaptation of cancer cells to anti-cancer drugs. In uneven weeks, 40000 UKF-NB-3 cells per cm2 were treated with the IC50 concentration of the selected drug. In even weeks, 4000 UKF-NB-3 cells per cm2 were allowed to grow in the absence of drug. We started to establish 10 cabazitaxel-, 10 epothilone B- and 10 paclitaxel-resistant UKF-NB-3 sub-lines by this approach. The paclitaxel-treated sub-lines displayed a trend towards decreased paclitaxel sensitivity relative to UKF-NB-3 after four and eight weeks, while the epothilone B- and cabazitaxel-treated sub-lines displayed a trend towards enhanced sensitivity to the respective drugs. In conclusion, our data suggest 1) that the repeated adaptation of a cell line to the same drug results in heterogenic sub-lines, 2) that the adaptation of a cancer cell line to a drug results in heterogeneity in the resulting resistant sub-line (as opposed to the selection of a pre-existing drug-resistant sub-population) and 3) that exposure of a cell population to different drugs with a similar mechanism of action may result in varying outcomes.

Item Type: Thesis (Master of Science by Research (MScRes))
Thesis advisor: Michaelis, Martin
Uncontrolled keywords: Neuroblastoma; Tubulin binding agents; resistance
Subjects: Q Science > QP Physiology (Living systems) > QP517 Biochemistry
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Users 1 not found.
Date Deposited: 13 Apr 2015 10:01 UTC
Last Modified: 29 May 2019 14:25 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/47953 (The current URI for this page, for reference purposes)
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