Abstract

Characteristic metabolic adaptations are recognized as a cancer hallmark. Breast cancer, like other cancer types, displays cellular respiratory switches—in particular, the Warburg effect—and important fluctuations in the glutamine and choline metabolisms. This cancer remains a world health issue mainly due to the side effects associated with chemotherapy, which force a reduction in the administered dose or even a complete discontinuation of the treatment. For example, Doxorubicin is efficient to treat breast cancer but unfortunately induces severe cardiotoxicity. In the present in vitro study, selected metabolic inhibitors were evaluated alone or in combination as potential treatments against breast cancer. In addition, the same inhibitors were used to possibly potentiate the effects of Doxorubicin. As a result, the combination of CB-839 (glutaminase inhibitor) and Oxamate (lactate dehydrogenase inhibitor) and the combination of CB-839/Oxamate/D609 (a phosphatidylcholine-specific phospholipase C inhibitor) caused significant cell mortality in both MDA-MB-231 and MCF-7, two breast cancer cell lines. Furthermore, all inhibitors were able to improve the efficacy of Doxorubicin on the same cell lines. Those findings are quite encouraging with respect to the clinical goal of reducing the exposure of patients to Doxorubicin and, subsequently, the severity of the associated cardiotoxicity, while keeping the same treatment efficacy.

Highlights

  • The aim of this study is to evaluate selected metabolic inhibitors on two breast cancer cell lines in order to determine their efficacy as a potential therapy in breast cancer

  • The loadings plot reveals that total Choline increase (tCho), glucose, glutamine and the amino acids are more concentrated in MCF-7 cells, while lactate, myo-inositol and glutamate are more present in MDA-MB-231 cells (Figure 1)

  • The metabolic reprograming in cancer cells has been demonstrated and added to the list of the cancer hallmarks, as well as apoptosis evading, angiogenesis or growth signal independence

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Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Cancer is reported as a major public health issue worldwide. Health Organization (WHO), 18.1 × 106 new cancers were diagnosed in 2018, and 9.6 × 106 patients died of their disease. These statistics could reach 26.4 × 106 new cancer cases and 17 × 106 related deaths per year in 2030. The main reasons behind this sad projected evolution are the increasing and aging world population, as well as the poor quality of life in some regions. The most frequently reported cancers are breast, prostate, lung and colon cancers [1]

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