Journal Article


J Keenan
M Clynes
P Meleady
M Henry
L Murphy



paclitaxel p glycoprotein carcinoma squamous cell lung neoplasms electrophoresis gel two dimensional genetics drug therapy neoplasm invasiveness cell adhesion proteomics metabolism docetaxel taxoids drug resistance neoplasm neoplasm proteins reactive oxygen species cell line tumor humans pharmacology antineoplastic agents phytogenic physiology physiopathology

Proteomic investigation of taxol and taxotere resistance and invasiveness in a squamous lung carcinoma cell line. (2007)

Abstract Pulse selections on a chemotherapy naive squamous lung carcinoma cell line, SKMES-1, with clinically relevant concentrations of taxanes (taxol or taxotere) resulted in the development of a stable taxotere-resistant variant, SKMES-1-Taxotere and an unstable taxol-resistant variant, SKMES-1-Taxol. Both variants exhibited increased invasiveness in vitro. The unstable nature of SKMES-1-Taxol facilitated looking at factors involved in loss of taxol resistance and increased invasion. The taxotere and taxol-resistant cell lines were 5.9-fold and 12.5-fold resistant to taxotere and taxol respectively. Alterations in expression of/or point mutations in tubulin, the main target of taxanes, is a major mechanism or resistance. However, alterations in expression of beta tubulin were not consistent in the taxane-selected variants. Cross-resistance to adriamycin, vincristine and etoposide (VP-16) was consistent with overexpression of P-glycoprotein (P-gp). However, P-gp alone is not sufficient to confer the complete multiple drug resistance phenotype as all cell lines exhibited cross-resistance to 5-Fluorouracil (5-FU) and more than one mechanism has been linked to taxane resistance. There was no correlation between the fall of taxol resistance in SKMES-1-Taxol and P-gp expression indicating the loss in resistance to be independent of P-gp expression. Furthermore, resistance to the other drugs was not unstable in SKMES-1-Taxol suggesting some parallel mechanisms of resistance. Two-dimensional electrophoresis coupled with matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry was used to identify alterations in expression of specific proteins associated with taxane resistance. A large number of differentially regulated proteins were identified in the resistant and invasive variants affecting cellular processes including stress response, protein turnover and cytoskeleton proteins.
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Full list of authors on original publication

J Keenan, M Clynes, P Meleady, M Henry, L Murphy

Experts in our system

Joanne Keenan
Dublin City University
Total Publications: 23
Martin Clynes
Dublin City University
Total Publications: 209
Paula Meleady
Dublin City University
Total Publications: 95
Michael Henry
Dublin City University
Total Publications: 78
Lisa Murphy
University College Dublin