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Cancer cell bioenergetics and pH regulation influence breast cancer cell resistance to paclitaxel and doxorubicin

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Abstract

The multidrug resistance (MDR) phenotype, frequently observed during cancer treatment, is often associated with drug efflux pump activity. However, many other factors are also known to be involved. Cancer cells often rely on aerobic glycolysis for energy production; this is known as the “Warburg effect” and is used as a survival mechanism. Associated to this event, a reverse pH gradient across the cell membrane occurs, leading to cytosol alkalinization and extracellular acidification. In the present study, we investigated the role of different mechanisms involved in MDR, such as altered tumor microenvironment and energetic metabolism. The breast cancer cell line MCF-7, used as model, was exposed to two widely used antitumor drugs, paclitaxel (antimitotic agent) and doxorubicin (alkylating agent). Cancer pH regulation was shown to be crucial for malignant characteristics such as cell migration and drug resistance. Our results showed that a lower extracellular pH induced a higher migratory capacity and higher resistance to the studied chemotherapeutical compounds in MCF-7 cells. Besides the influence of the extracellular pH, the role of the tumor metabolism in the MDR phenotype was also investigated. Pre-treatment with different bioenergetic modulators led to cell ATP depletion and altered lactic acid production and glucose consumption, resulting in increased sensitivity to paclitaxel and doxorubicin. Overall, this study supports the potential use of compounds targeting cell metabolism and tumor microenvironment factors such as pH, as co-adjuvants in conventional chemotherapy.

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Authors and Affiliations

  1. CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra, 1317, 4585-116, Gandra, PRD, Portugal

    Diana Tavares-Valente, Roxana Moreira & Odília Queirós

  2. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

    Fátima Baltazar

  3. ICVS/3B’s—PT Government Associate Laboratory, Braga, Guimarães, Portugal

    Fátima Baltazar

  4. CBMA—Center of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, Braga, 4710-057, Portugal

    Roxana Moreira & Odília Queirós

Authors
  1. Diana Tavares-Valente
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  2. Fátima Baltazar
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  3. Roxana Moreira
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  4. Odília Queirós
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Correspondence to Odília Queirós.

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Tavares-Valente, D., Baltazar, F., Moreira, R. et al. Cancer cell bioenergetics and pH regulation influence breast cancer cell resistance to paclitaxel and doxorubicin. J Bioenerg Biomembr 45, 467–475 (2013). https://doi.org/10.1007/s10863-013-9519-7

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  • DOI: https://doi.org/10.1007/s10863-013-9519-7

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