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

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 fluorescence-based 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/ 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. 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. Electronic supplementary material The online version of this article (10.1186/s12885-019-5939-z) contains supplementary material, which is available to authorized users.

Blockage of AMPK-ULK1 pathway mediated autophagy promotes cell apoptosis to increase doxorubicin sensitivity in breast cancer (BC) cells: an in vitro study

“…Doxorubicin (Dox) was commonly used for breast cancer (BC) treatment in clinic [6][7][8], however, the therapeutic e cacy of this chemical drug was seriously limited as the results of drug resistance [9,10], resulting in worse prognosis and recurrence in BC patients [11]. Recent data indicated that combination treatment strategies might be novel to increase Dox-sensitivity for BC treatment [7,12], hence, the present study managed to investigate this issue in vitro.…”

“…Among all the chemotherapeutic drugs, doxorubicin (Dox) was commonly used for cancer treatment, including non-small cell lung cancer (NSCLC) [3], ovarian cancer [4], hepatocellular carcinoma (HCC) [5], BC [6][7][8], etc.. However, Dox-resistance had became an insurmountable obstacle for cancer treatment [9,10], which made this drug "ineffectiveness" for BC treatment, resulting in worse prognosis and recurrence in BC patients [11]. To solve this problem, the combination treatment had been developed by researchers to increase Dox-sensitivity [7,12].…”

Survivin Suppression Strengthens BZML-induced Mitotic Catastrophe to Overcome Multidrug Resistance by Removing Senescent A549/Taxol Cells

“…Despite considerable research efforts aimed at developing novel therapeutic approaches against NSCLC, including molecularly targeted therapy and immunotherapy, the frequency of MDR severely restricts the effectiveness of various anticancer drugs [3,4] . Currently, apoptosis tolerance-mediated MDR has been considered the most common and complex drug-resistant mechanism [5,33] . However, in addition to apoptosis, anticancer drugs can also trigger other anticancer mechanisms, such as autophagy, MC, ferroptosis, pyroptosis, necrosis and senescence, to inhibit the proliferation of cancer cells and kill them by avoiding the apoptosis-resistant pathway [11,17,34,35] .…”

In vitroevolution and whole genome analysis to study chemotherapy drug resistance in haploid human cells

“…Our next objective was to create drug resistant lines. Although we have had difficulty creating resistant lines for some drugs in some species ("irresistibles" (24)), there is precedent for resistance to the drugs included here (25)(26)(27). To reduce the possibility of selecting mutations that were present in a nonhomogenous population of HAP-1 cells and to facilitate later genomic analysis, we first cloned the cells.…”