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Mechanism of cell death in drug resistant human breast cancer cells.

Ajabnoor, Ghada. (2010) Mechanism of cell death in drug resistant human breast cancer cells. Doctoral thesis, University of Surrey (United Kingdom)..

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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.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors :
Ajabnoor, Ghada.
Date : 2010
Contributors :
Depositing User : EPrints Services
Date Deposited : 09 Nov 2017 12:11
Last Modified : 16 Mar 2018 17:32

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