Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model

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dc.contributor.authorChristowitz, Claudiaen_ZA
dc.contributor.authorDavis, Tanja Andreaen_ZA
dc.contributor.authorIsaacs, Ashwinen_ZA
dc.contributor.authorVan Niekerk, Gustaven_ZA
dc.contributor.authorHattingh, Suzelen_ZA
dc.contributor.authorEngelbrecht, Anna-Marten_ZA
dc.date.accessioned2019-08-05T06:18:30Z
dc.date.available2019-08-05T06:18:30Z
dc.date.issued2019-08-01
dc.date.updated2019-08-04T03:19:23Z
dc.descriptionCITATION: 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.
dc.descriptionThe original publication is available at https://bmccancer.biomedcentral.com
dc.description.abstractBackground: 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.
dc.description.urihttps://bmccancer.biomedcentral.com/articles/10.1186/s12885-019-5939-z
dc.description.versionPublisher's version
dc.format.extent10 pages ; illustrations
dc.identifier.citationChristowitz, 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
dc.identifier.issn1471-2407 (online)
dc.identifier.otherdoi:10.1186/s12885-019-5939-z
dc.identifier.urihttp://hdl.handle.net/10019.1/106340
dc.language.isoen_ZAen_ZA
dc.publisherBMC (part of Springer Nature)
dc.rights.holderAuthors retain copyright
dc.subjectBreast cancer
dc.subjectDoxorubicin -- Side effectsen_ZA
dc.subjectDrug resistance in cancer cellsen_ZA
dc.titleMechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour modelen_ZA
dc.typeArticle
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