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

// Ritu Arora 1 , David Schmitt 1 , Balasubramanyam Karanam 2 , Ming Tan 1 , Clayton Yates 2 , Windy Dean-Colomb 1, 3 1 Department of Oncologic Sciences, University of South Alabama Mitchell Cancer Institute, Mobile, AL 36604, USA 2 Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA 3 Department of Oncologic Research, University Hospital and Clinics, Lafayette General Health, Lafayette, LA 70503, USA Correspondence to: Windy Dean-Colomb, e-mail: wmdeancolomb@lgh.com Keywords: Warburg effect, Metabolism, Panepoxydone, LDH-A, LDH-B, Breast cancer Received: August 15, 2014      Accepted: November 02, 2014      Published: January 07, 2015 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.