Abstract
BackgroundDoxorubicin 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.MethodsA 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 fluorescence-based immunohistochemistry.ResultsDoxorubicin 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/ extracellular-signal-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.ConclusionsOur 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.
Highlights
Doxorubicin is currently the most effective chemotherapeutic drug used to treat breast cancer
Previous studies have shown that the efficacy of doxorubicin can be improved by inhibition of the extracellularsignal-regulated kinase (ERK) signalling pathway and thereby treatment failure can be overcome [6, 24,25,26]
The tumours grew rapidly over the study period and showed resistance to both DXR doses. Analyses revealed that both low dose (LD)-DXR and high dose (HD)-DXR groups has a significantly increased tumour volume when compared to the tumour control (TC) group (Fig. 1)
Summary
Doxorubicin is currently the most effective chemotherapeutic drug used to treat breast cancer. Studies reported that the interaction between signalling pathways can promote drug resistance through the induction of proliferation, cell cycle progression and prevention of apoptosis. Doxorubicin (DXR) is part of the anthracycline family and is currently the most effective chemotherapeutic drug used to treat breast cancer [3, 4] It has, been shown that DXR can induce drug resistance and even tumour growth resulting in poor patient prognosis and survival [5,6,7]. Studies reported that the interaction between signalling pathways can promote DXR resistance through the induction of proliferation, cell cycle progression and prevention of apoptosis [5, 9, 10]
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