Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model
Date
2019-08-01
Journal Title
Journal ISSN
Volume Title
Publisher
BMC (part of Springer Nature)
Abstract
Background: Doxorubicin is currently the most effective chemotherapeutic drug used to treat breast cancer. It has,
however, been shown that doxorubicin can induce drug resistance resulting in poor patient prognosis and survival.
Studies reported that the interaction between signalling pathways can promote drug resistance through the
induction of proliferation, cell cycle progression and prevention of apoptosis. The aim of this study was therefore to
determine the effects of doxorubicin on apoptosis signalling, autophagy, the mitogen-activated protein kinase
(MAPK)- and phosphoinositide 3-kinase (PI3K)/Akt signalling pathway, cell cycle control, and regulators of the
epithelial-mesenchymal transition (EMT) process in murine breast cancer tumours.
Methods: A tumour-bearing mouse model was established by injecting murine E0771 breast cancer cells,
suspended in Hank’s Balances Salt Solution and Corning® Matrigel® Basement Membrane Matrix, into female C57BL/
6 mice. Fourty-seven mice were randomly divided into three groups, namely tumour control (received Hank’s
Balances Salt Solution), low dose doxorubicin (received total of 6 mg/ml doxorubicin) and high dose doxorubicin
(received total of 15 mg/ml doxorubicin) groups. A higher tumour growth rate was, however, observed in
doxorubicin-treated mice compared to the untreated controls. We therefore compared the expression levels of
markers involved in cell death and survival signalling pathways, by means of western blotting and fluorescencebased
immunohistochemistry.
Results: Doxorubicin failed to induce cell death, by means of apoptosis or autophagy, and cell cycle arrest,
indicating the occurrence of drug resistance and uncontrolled proliferation. Activation of the MAPK/ extracellularsignal-
regulated kinase (ERK) pathway contributed to the resistance observed in treated mice, while no significant
changes were found with the PI3K/Akt pathway and other MAPK pathways. Significant changes were also observed
in cell cycle p21 and DNA replication minichromosome maintenance 2 proteins. No significant changes in EMT
markers were observed after doxorubicin treatment.
Conclusions: Our results suggest that doxorubicin-induced drug resistance and tumour growth can occur through
the adaptive role of the MAPK/ERK pathway in an effort to protect tumour cells. Previous studies have shown that
the efficacy of doxorubicin can be improved by inhibition of the ERK signalling pathway and thereby treatment
failure can be overcome.
Description
CITATION: Christowitz, C., et al. 2019. Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model. BMC Cancer, 19:757, doi:10.1186/s12885-019-5939-z.
The original publication is available at https://bmccancer.biomedcentral.com
The original publication is available at https://bmccancer.biomedcentral.com
Keywords
Breast cancer, Doxorubicin -- Side effects, Drug resistance in cancer cells
Citation
Christowitz, C., et al. 2019. Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model. BMC Cancer, 19:757, doi:10.1186/s12885-019-5939-z