Metabolomics Analysis Reveals Altered Metabolic Pathways and Response to Doxorubicin in Drug-Resistant Triple-Negative Breast Cancer Cells
This study aimed to investigate metabolic changes following the acquisition of resistance to doxorubicin in the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Two drug-resistant cell lines, DOX-RES-50 and DOX-RES-100, were generated by treating MDA-MB-231 cells with doxorubicin for 24 h...
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| Format: | Article |
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MDPI AG
2023-07-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/13/7/865 |
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| author | Blake R. Rushing Sabrina Molina Susan Sumner |
| author_facet | Blake R. Rushing Sabrina Molina Susan Sumner |
| author_sort | Blake R. Rushing |
| collection | DOAJ |
| description | This study aimed to investigate metabolic changes following the acquisition of resistance to doxorubicin in the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Two drug-resistant cell lines, DOX-RES-50 and DOX-RES-100, were generated by treating MDA-MB-231 cells with doxorubicin for 24 h and allowing them to recover for six weeks. Both drug-resistant cell lines demonstrated an increase in doxorubicin IC<sub>50</sub> values, indicating acquired drug resistance. Metabolomics analysis showed clear separation between the parental MDA-MB-231 cell line and the drug-resistant cell lines. Pathway analysis revealed that arginine and proline metabolism, glutathione metabolism, and beta-alanine metabolism were significantly perturbed in the drug-resistant cell lines compared to the parental cell line. After matching signals to an in-house library of reference standards, significant decreases in short- and medium-chain acylcarnitines and significant increases in long-chain acylcarnitines, 5-oxoproline, and 7-ketodeoxycholic acid were observed in the resistant cell lines as compared to the parental MDA-MB-231 cell line. In addition to baseline metabolic differences, we also investigated differences in metabolic responses in resistant cell lines upon a second exposure at multiple concentrations. Results indicate that whereas the parental MDA-MB-231 cell line had many metabolites that responded to doxorubicin in a dose-dependent manner, the two resistant cell lines lost a dose-dependent response for the majority of these metabolites. The study’s findings provide insight into how metabolism is altered during the acquisition of resistance in TNBC cells and how the metabolic response to doxorubicin changes upon repeated treatment. This information can potentially identify novel targets to prevent or reverse multi-drug resistance in TNBC, and also demonstrate the usefulness of metabolomics technology in identifying new mechanisms of drug resistance in cancer and potential drug targets. |
| first_indexed | 2024-03-11T00:50:10Z |
| format | Article |
| id | doaj.art-bf077e9c46614093a47303914e77c7b5 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-11T00:50:10Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-bf077e9c46614093a47303914e77c7b52023-11-18T20:28:20ZengMDPI AGMetabolites2218-19892023-07-0113786510.3390/metabo13070865Metabolomics Analysis Reveals Altered Metabolic Pathways and Response to Doxorubicin in Drug-Resistant Triple-Negative Breast Cancer CellsBlake R. Rushing0Sabrina Molina1Susan Sumner2Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USANutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USADepartment of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAThis study aimed to investigate metabolic changes following the acquisition of resistance to doxorubicin in the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Two drug-resistant cell lines, DOX-RES-50 and DOX-RES-100, were generated by treating MDA-MB-231 cells with doxorubicin for 24 h and allowing them to recover for six weeks. Both drug-resistant cell lines demonstrated an increase in doxorubicin IC<sub>50</sub> values, indicating acquired drug resistance. Metabolomics analysis showed clear separation between the parental MDA-MB-231 cell line and the drug-resistant cell lines. Pathway analysis revealed that arginine and proline metabolism, glutathione metabolism, and beta-alanine metabolism were significantly perturbed in the drug-resistant cell lines compared to the parental cell line. After matching signals to an in-house library of reference standards, significant decreases in short- and medium-chain acylcarnitines and significant increases in long-chain acylcarnitines, 5-oxoproline, and 7-ketodeoxycholic acid were observed in the resistant cell lines as compared to the parental MDA-MB-231 cell line. In addition to baseline metabolic differences, we also investigated differences in metabolic responses in resistant cell lines upon a second exposure at multiple concentrations. Results indicate that whereas the parental MDA-MB-231 cell line had many metabolites that responded to doxorubicin in a dose-dependent manner, the two resistant cell lines lost a dose-dependent response for the majority of these metabolites. The study’s findings provide insight into how metabolism is altered during the acquisition of resistance in TNBC cells and how the metabolic response to doxorubicin changes upon repeated treatment. This information can potentially identify novel targets to prevent or reverse multi-drug resistance in TNBC, and also demonstrate the usefulness of metabolomics technology in identifying new mechanisms of drug resistance in cancer and potential drug targets.https://www.mdpi.com/2218-1989/13/7/865metabolomicstriple-negative breast cancerdrug resistancedoxorubicinchemotherapy |
| spellingShingle | Blake R. Rushing Sabrina Molina Susan Sumner Metabolomics Analysis Reveals Altered Metabolic Pathways and Response to Doxorubicin in Drug-Resistant Triple-Negative Breast Cancer Cells Metabolites metabolomics triple-negative breast cancer drug resistance doxorubicin chemotherapy |
| title | Metabolomics Analysis Reveals Altered Metabolic Pathways and Response to Doxorubicin in Drug-Resistant Triple-Negative Breast Cancer Cells |
| title_full | Metabolomics Analysis Reveals Altered Metabolic Pathways and Response to Doxorubicin in Drug-Resistant Triple-Negative Breast Cancer Cells |
| title_fullStr | Metabolomics Analysis Reveals Altered Metabolic Pathways and Response to Doxorubicin in Drug-Resistant Triple-Negative Breast Cancer Cells |
| title_full_unstemmed | Metabolomics Analysis Reveals Altered Metabolic Pathways and Response to Doxorubicin in Drug-Resistant Triple-Negative Breast Cancer Cells |
| title_short | Metabolomics Analysis Reveals Altered Metabolic Pathways and Response to Doxorubicin in Drug-Resistant Triple-Negative Breast Cancer Cells |
| title_sort | metabolomics analysis reveals altered metabolic pathways and response to doxorubicin in drug resistant triple negative breast cancer cells |
| topic | metabolomics triple-negative breast cancer drug resistance doxorubicin chemotherapy |
| url | https://www.mdpi.com/2218-1989/13/7/865 |
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