Exp Clin Endocrinol Diabetes 2012; 120 - A22
DOI: 10.1055/s-0032-1330817

3-bromopyruvate cytotoxic effect in breast cancer cells is dependent of monocarboxylate transporters (MCT) expression and is enhanced by butyrate

A Pacheco 1, 2, O Queirós 1, 2, A Preto 2, C Pinheiro 3, 4, J Azevedo-Silva 2, R Moreira 1, M Pedro 1, F Baltazar 3, 4, M Casal 2
  • 1Centro de Investigação em Ciências da Saúde (CICS), Instituto Superior de Ciências da Saúde-Norte, CESPU Gandra PRD, Portugal
  • 2CBMA – Center of Molecular and Environmental Biology, University of Minho, Braga, Portugal
  • 3Life and Health Sciences Research Institute (ICVS)/School of Health Sciences/University of Minho, Braga, Portugal
  • 4ICVS/3B's, Braga/Guimarães, Portugal

Most cancers exhibit the “Warburg effect”, consisting in increased glycolysis rates and lactate production, even in the presence of oxygen. Monocarboxylate transporters (MCTs) mediate lactate efflux through the plasma membrane. 3-bromopyruvate (3-BP) is an energetic inhibitor, with high anti-tumor efficiency either in rodent models or in humans. Being a pyruvate and lactate analogue, is likely to be transported by the same permeases, the monocarboxylate transporters (MCTs), which are upregulated in several cancer cells. In the present study, we aimed at determining the effect of 3-BP in three breast cancer cell lines (ZR-75–1, MCF-7 and SK-BR-3) and evaluate the putative role of MCTs on its cytotoxic effect.

The three cell lines showed different sensitivities for 3-BP: ZR-75–1> MCF-7> SK-BR-3. 3-BP reduced the lactate production, induced cell morphological alterations and increased apoptosis. Furthermore, 3-BP appear to be cytotoxic rather than cytostatic, as a decrease in cell viability was observed along time after removal of 3-BP. Pre-incubation of the cells with butyrate, but not with lactate, pyruvate or acetate, significantly increased 3-BP cytotoxicity, especially in the most resistant cell line, SK-BR-3. Additionally, it was observed in this cell line that butyrate pre-treatment induced localization of MCT1 in the plasma membrane and led to an increased expression of MCT4 and its chaperone CD147. These conditions appear to stimulate the overall capacity of the cell to transport 3-BP, thus enhancing its cytotoxicity.

The overall results suggest that MCTs are involved in 3-BP mechanism of action, possibly mediating its uptake into the cell. Pre-treatment with butyrate enhanced 3-BP effect, most probably increasing the rates of 3-BP transport through MCT1/MCT4. This study supports the potencial use of butyrate pre-treatment as adjuvant of 3-BP in the treatment of breast cancer resistant cells.

This work was funded by the project CESPU-03-GBMC-CICS-11