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Restricting Anaerobic Glycolysis Reliance (Warburg effect): Novel Natural Products Based Therapeutic Strategy for Cancer Treatment.

Robert Gallagher, Noboru Motohashi, Anuradha Vanam, Rao Gollapudi

Compared to normal cells, cancer cells depend on the generation of excessive amounts of metabolic energy to induce cellular proliferation and metastatic growth. In the presence of oxygen, normal cells predominantly utilize mitochondrial oxidative phosphorylation; whereas cancer cells rely on the anaerobic glycolysis pathway-converting glucose to lactate-to fulfil their respective energetic requirements. This preference by cancer cells towards the anaerobic glycolysis process in normal oxygen level environments is known as the “Warburg effect”. The phosphatidylinositol-3 kinase (PI3K) and AMP-activated kinase (AMPK) pathways play important roles in aerobic glycolytic signaling and regulation. Specifically, the PI3k pathway regulates glycolysis-through AKT1 protein kinase (AKT1) and mTOR signaling-thereby activating the hypoxia inducible transcription factor (HIF-1) response. Furthermore, AMPK controls cell proliferation under metabolic stress conditions, where active AMKP inhibits mammalian target of rapamycin (mTOR) activity. The elevated anaerobic glycolysis levels among many tumors are hypoxic and the glycolysis inhibitors have potential applications in curbing cancer proliferation and metastasis. Several natural products target various proteins participating in cellular glycolysis, by interfering with the glycolytic signaling pathways. Numerous natural products with diverse structural characteristics have been identified as potential targets to restrict aerobic glycolysis in cancer cells. Recently, 2-deoxy-D-glucose (1), 3-bromopyruvate (2), 3-bromo-2-oxopropionate-1-propyl ester (3), 5-thioglucose (4) and dichloroacetic acid (5) were investigated as potential glycolysis inhibitors. Furthermore, natural product compound classes-such as alkaloids flavonoids, polyphenols, quinones, and terpenoids-showed promising anticancer and anti-metastatic activities, through the restriction of aerobic glycolysis, and promotion of anaerobic glycolysis in cancer cells.