Discovery of Novel Doxorubicin Metabolites in MCF7 Doxorubicin-Resistant Cells.

Xu Wang,Jian Jin,Yun Chen,Wentao Wang,Renjie Hui,Xiaohai Gong,Yujiao Chen

doi:10.3389/fphar.2019.01434

Abstract

Doxorubicin (DOX) is metabolized to a variety of metabolites in vivo, which has been shown to be associated with cardiotoxicity. We speculate that metabolic processes are also present in tumor cells. A LC-MS/MS method was developed to detect intracellular metabolites. Drug resistant tumor cells with high drug stress tolerance and metabolically active are suitable as materials for this study. Our results show difference in drug metabolites between the wild-type and drug-resistant cells. Three novel doxorubicin metabolites were discovered after the LC-MS/MS analysis. All these metabolites and their profiles of metabolites are totally different from that in liver or kidney in vivo. Our results suggest that tumor cells and drug-resistant tumor cells have a unique drug metabolism pathway for doxorubicin.

Highlights

Some chemotherapeutic drugs need to enter the target tumor cells to produce cytotoxic effects
We found that doxorubicin accumulated in the cytosol of doxorubicin-resistant breast cancer cell line MCF7/DOX, whereas in the sensitive cell MCF7/WT doxorubicin is concentrated in the nucleus (Ma et al, 2012)
Since MCF7 and MCF7/DOX have different sensitivities to doxorubicin, we treated them with 18μg/ml and 100μg/ml doxorubicin, respectively, to ensure that the cells survived during a short period of drug treatment

Summary

Introduction

Some chemotherapeutic drugs need to enter the target tumor cells to produce cytotoxic effects. The forms of intracellular drugs are important for the pharmacological effects and the occurrence of drug resistance. It was found that intracellular drugs bind to various proteins and affect their function (Chen et al, 2017). Enzymes that bind to drugs may alter the cytotoxicity of the drug. The existing drug metabolism researches mainly focus on the absorption, distribution, and chemical structure changes of drugs in vivo, with reduced pharmacological activity, or increased polarity to be more excreted after metabolism. It is possible that the drugs are partially metabolized in the tumor cells to cause properties changes. We have developed a method for analyzing intracellular drug metabolism in tumor cells

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Results

Conclusion