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ABCG2-Associated Resistance to Hoechst 33342 and Topotecan in a Murine Cell Model with Constitutive Expression of Side Population Characteristics

Smith, Paul James, Furon, Emeline, Wiltshire, Marie, Campbell, Lee, Feeney, Graham P., Snyder, R. D. and Errington, Rachel Jane 2009. ABCG2-Associated Resistance to Hoechst 33342 and Topotecan in a Murine Cell Model with Constitutive Expression of Side Population Characteristics. Cytometry Part A 75A (11) , pp. 924-933. 10.1002/cyto.a.20800

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Abstract

Drug resistant tumor “side-populations,” enriched in cancer stem cells and identified by reduced accumulation of Hoechst 33342 under ABCG2-mediated efflux, may compromise therapeutic outcome. Side-population cells have predicted resistance to minor groove ligands, including the DNA topoisomerase I poison topotecan. We have used a stable Hoechst 33342-resistant murine L cell system (HoeR415) to study resistance patterns, removing the need for SP isolation before microarray analysis of gene expression and the tracking of cell cycle dynamics and cytotoxicity. The majority of HoeR415 cells displayed a side-population phenotype comparable with that of the side-population resident in the ABCG2 over-expressing A549 lung cancer cell line. Photo-crosslinking showed direct protection against minor groove ligand residence on DNA, driven by ABCG2-mediated efflux and not arising from any binding competition with endogenous polyamines. The covalent minor-groove binding properties of the drug FCE24517 (tallimustine) prevented resistance suggesting a mechanism for overcoming SP-related drug resistance. Hoechst 33342-resistant murine cells showed lower but significant crossresistance to topotecan, again attributable to enhanced ABCG2 expression, enabling cells to evade S-phase arrest. Hoechst 33342/TPT-resistant cells showed limited ancillary gene expression changes that could modify cellular capacity to cope with chronic stress including over-expression of Aldh1a1 and Mgst1, but under-expression of Plk2 and Nnt. There was no evidence to link the putative stem cell marker ALDH1A1 with any augmentation of the TPT resistance phenotype. The study has implications for the patterns of drug resistance arising during tumor repopulation and the basal resistance to minor groove-binding drugs of tumor side-populations. © 2009 International Society for Advancement of Cytometry

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > R Medicine (General)
Uncontrolled Keywords: ABCG2; topotecan; side population; Hoechst 33342; lung cancer; drug resistance
Publisher: Wiley-Blackwell
ISSN: 1552-4922
Last Modified: 05 Nov 2019 03:39
URI: http://orca-mwe.cf.ac.uk/id/eprint/37110

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