Modulating bioenergetic metabolism for cancer therapy

VILLAVERDE M. S.

Congreso; Reunion Anual SAIC 2016; 2016

Cancer cells increase glucose uptake, even in the presence of adequate oxygen levels. This phenomenon is known as the Warburg effect and suggests a dependency on glycolysis, especially in rapidly growing tumors. Thus, it becomes cancer cell metabolism an attractive area of clinical and pre-clinical therapy developments. Metformin (MET) is a biguanide, clinically known as an oral well tolerated anti-diabetic drug. Numerous recent studies show that MET decreases cancer cell viability and tumor growth in different xenograft models. Furthermore, retrospective epidemiological studies revealed a decrease in the incidence of cancer in diabetic patients treated with MET. Apparently, MET modulates cell metabolism at different cell levels since MET increases glycolysis, inhibits respiratory chain complex I and ultimately inhibits mTOR leading to growth arrest and apoptosis. However, the molecular mechanisms underlying MET antitumor effects remains unclear. On the other hand, 2-deoxyglucose (2DG) is a reversible inhibitor of hexokinase, the first and rate-limiting enzyme of glycolysis. The inhibition of glycolysis decreases the production of glycolytic intermediates, which are the precursors of nucleic acids and phospholipids. In addition, depletion of glucose-6-phosphate also decreases pentose phosphate pathway (PPP) and consequently the antioxidant defenses of cancer cells. At present, different studies explored the combination of 2DG with chemotherapy as sensitizer. Here, we will describe the potential antitumor effect and the mechanism involve in the effectiveness of modulating bioenergetic pathways by MET in combination with 2DG or 6-aminonicotinamide (6AN, PPP inhibitor) on feline mammary carcinoma and melanoma cell lines as a preclinical approach of both veterinary and human disease.