Inhibition of the Warburg effect with a natural compound reveals a novel measurement for determining the metastatic potential of breast cancers.

Abstract

Metabolism is an important differentiating feature of cancer cells. Lactate dehydrogenases (LDH) A/B are metabolically important proteins and are involved in the critical step of inter-conversion of lactate to pyruvate. Panepoxydone (PP), a natural NF-kB inhibitor, significantly reduces the oxygen consumption and lactate production of MCF-7 and triple negative (MDA-MB-231, MDA-MB-468 and MDA-MB-453) breast cancer cells. We further observed that PP inhibited mitochondrial membrane potential and the ATP synthesis using flow cytometry. PP also up-regulated LDH-B and down-regulated LDH-A expression levels in all breast cancer cells to similar levels observed in HMEC cells. Over-expression of LDH-B in cancer cell lines leads to enhanced apoptosis, mitochondrial damage, and reduced cell migration. Analyzing the patient data set GDS4069 available on the GEO website, we observed 100% of non TNBC and 60% of TNBC patients had less LDH-B expression than LDH-A expression levels. Herein we report a new term called Glycolytic index, a novel method to calculate utilization of oxidative phosphorylation in breast cancer cells through measuring the ratio of the LDH-B to LDH-A. Furthermore, inhibitors of NF-kB could serve as a therapeutic agent for targeting metabolism and for the treatment of triple negative breast cancer.

• Authors: Ritu Arora, David Schmitt, Balasubramanyam Karanam, Ming Tan, Clayton Yates, Windy Dean-Colomb
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 2 Pg. 662-78 (Jan 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25575825 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• panepoxydone
• Adenosine Triphosphate
• L-Lactate Dehydrogenase

Topics

• Adenosine Triphosphate (antagonists & inhibitors, biosynthesis)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Glycolysis (drug effects)
• Humans
• L-Lactate Dehydrogenase (biosynthesis, metabolism)
• MCF-7 Cells
• Membrane Potential, Mitochondrial (drug effects)
• Neoplasm Metastasis
• Oxidative Phosphorylation
• Signal Transduction
• Triple Negative Breast Neoplasms (drug therapy, metabolism, pathology)