Affiliation:
1. Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2. Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA
Abstract
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 IC50 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.
Funder
Sumner Lab
University of North Carolina’s Nutrition Research Institute
National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health
Subject
Molecular Biology,Biochemistry,Endocrinology, Diabetes and Metabolism
Reference40 articles.
1. Cancer statistics, 2023;Siegel;CA Cancer J. Clin.,2023
2. Triple negative breast cancer: Pitfalls and progress;Zagami;Breast Cancer,2022
3. Resistance to neoadjuvant chemotherapy in triple negative breast cancer mediated by a reversible drug-tolerant state;Echeverria;Sci. Transl. Med.,2019
4. Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response;Lips;Breast Cancer Res.,2015
5. Tan, S.H., Sabrina Sapari, N., Miao, H., Hartman, M., Loh, M., Chng, W.J., Iau, P., Ahmad Buhari, S., Soong, R., and Lee, S.C. (2015). High-throughput mutation profiling changes before and 3 weeks after chemotherapy in newly diagnosed breast cancer patients. PLoS ONE, 10.
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献