Loss of O-6-methylguanine-DNA methyltransferase confers collateral sensitivity to carmustine in topoisomerase II-mediated doxorubicin resistant triple negative breast cancer cells

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Title: Loss of O-6-methylguanine-DNA methyltransferase confers collateral sensitivity to carmustine in topoisomerase II-mediated doxorubicin resistant triple negative breast cancer cells
Authors: Raguz, S
Adams, C
Masrour, N
Rasul, S
Papoutsoglou, P
Hu, Y
Cazzanelli, G
Zhou, Y
Patel, N
Coombes, C
Yaguee, E
Item Type: Journal Article
Abstract: Triple-negative breast cancer is characterized by aggressive tumours whose cells lack oestrogen and progesterone receptors and do not over-express HER2. It accounts for approximately 10–15% of breast cancer cases. We sought to generate a cellular model of chemotherapy drug resistance for this type of disease to provide the tools for the development of new therapies. Doxorubicin is a component of some chemotherapy regimes used to treat this form of cancer but resistance preventing disease eradication frequently occurs, mainly due to over-expression of drug transporters such as P-glycoprotein. CALDOX cells were generated by exposure of CAL51 to doxorubicin. Resistance to doxorubicin did not involve drug transporters, as the both parental and resistant cells accumulated doxorubicin to comparable levels. CALDOX cells had slower proliferation rate and an extended G1 cell cycle stage than the parental line, mainly due to an intrinsic activation of CDNK1 (p21), but this cell cycle block was not involved in the mechanism of resistance. CALDOX cells had reduced levels of TOP2A (topoisomerase IIα) and were cross resistant to the topoisomerase II inhibitors etoposide and mitoxantrone. CALDOX cells showed collateral sensitivity to carmustine due to the lack of O6-methylguanine-DNA-methyltransferase (MGMT) expression, related to the hypermethylation of its promoter. The collateral sensitivity of CALDOX cells to carmustine provides the rationale to evaluate MGMT promoter methylation status to design better therapeutic strategies for triple negative breast cancer.
Issue Date: 15-Jan-2013
Date of Acceptance: 22-Oct-2012
URI: http://hdl.handle.net/10044/1/69163
DOI: https://dx.doi.org/10.1016/j.bcp.2012.10.020
ISSN: 0006-2952
Publisher: Elsevier
Start Page: 186
End Page: 196
Journal / Book Title: Biochemical Pharmacology
Volume: 85
Issue: 2
Copyright Statement: © 2013 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: C37/A12011
Keywords: Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Triple negative breast cancer
Collateral sensitivity
TOP2A
MGMT
MULTIDRUG-RESISTANCE
P-GLYCOPROTEIN
IN-VITRO
DRUG
EXPRESSION
GENE
CHEMOTHERAPY
APOPTOSIS
IDENTIFICATION
ALPHA
Antigens, Neoplasm
Antineoplastic Agents
Biological Transport
Breast Neoplasms
Carmustine
Cell Line, Tumor
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p21
DNA Methylation
DNA Topoisomerases, Type II
DNA-Binding Proteins
Doxorubicin
Drug Resistance, Neoplasm
Female
G1 Phase
Gene Expression Regulation, Neoplastic
Humans
Inhibitory Concentration 50
Neoplasm Proteins
O(6)-Methylguanine-DNA Methyltransferase
Poly-ADP-Ribose Binding Proteins
Promoter Regions, Genetic
Recombinant Proteins
Topoisomerase II Inhibitors
Tumor Suppressor Protein p53
1115 Pharmacology and Pharmaceutical Sciences
Publication Status: Published
Online Publication Date: 2012-10-30
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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