Galloflavin, a New Lactate Dehydrogenase Inhibitor, Induces the Death of Human Breast Cancer Cells With Different Glycolytic Attitude by Affecting Distinct Signaling Pathways

Eur J Pharm Sci. 2012 Nov 20;47(4):729-38. doi: 10.1016/j.ejps.2012.08.012. Epub 2012 Aug 30.

Abstract

Galloflavin (GF), a recently identified lactate dehydrogenase inhibitor, hinders the proliferation of cancer cells by blocking glycolysis and ATP production. The aim of the present experiments was to study the effect of this compound on breast cancer cell lines reproducing different pathological subtypes of this tumor: MCF-7 (the well differentiated form), MDA-MB-231 (the aggressive triple negative tumor) and MCF-Tam (a sub-line of MCF-7 with acquired tamoxifen resistance). We observed marked differences in the energetic metabolism of these cell lines. Compared to MCF-7 cells, both MDA-MB-231 and MCF-Tam cells exhibited higher LDH levels and glucose uptake and showed lower capacity of oxygen consumption. In spite of these differences, GF exerted similar growth inhibitory effects. This result was explained by the finding of a constitutively activated stress response in MDA-MB-231 and MCF-Tam cells, which reproduce the poor prognosis tumor forms. As a further proof, different signaling pathways were found to be involved in the antiproliferative action of GF. In MCF-7 cells we observed a down regulation of the ERα-mediated signaling needed for cell survival. On the contrary, in MCF-Tam and MDA-MB-231 cells growth inhibition appeared to be contributed by an oxidative stress condition. The prevalent mechanism of cell death was found to be apoptosis induction. Because of the clinical relevance of breast cancer forms having the triple negative and/or chemoresistant phenotype, our results showing comparable effects of GF even on aggressively growing cells encourage further studies to verify the potential of this compound in improving the chemotherapy of breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / metabolism
  • Cell Death / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Energy Metabolism / drug effects
  • Female
  • Glucose / metabolism
  • Glycolysis / drug effects
  • Humans
  • Isocoumarins / pharmacology*
  • L-Lactate Dehydrogenase / antagonists & inhibitors*
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • MCF-7 Cells
  • Oxidative Stress / drug effects
  • Oxygen Consumption / drug effects
  • Signal Transduction / drug effects

Substances

  • Isocoumarins
  • galloflavin
  • L-Lactate Dehydrogenase
  • Glucose