Inhibition of 6-phosphofructo-2-kinase suppresses breast tumor growth in vivo.

Abstract

Abstract Abstract #3064 Phosphofructo-1-kinase, a rate-limiting enzyme of glycolysis, is activated in neoplastic cells by fructose-2,6-bisphosphate (Fru-2,6-BP), a product of four 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isozymes (PFKFB1-4). The inducible PFKFB3 isozyme is constitutively expressed by neoplastic cells and required for the high glycolytic rate and anchorage-independent growth of ras-transformed cells. We report that siRNA silencing or small molecule inhibition (3PO) of PFKFB3 causes a decrease in cell proliferation and metabolic flux in several breast cancer cell lines (MDA-MB-231, MDA-MB-468, BT-549, BT-474, SK-BR-3, ZR-75-1, MCF-7, and MCF-10A). Furthermore, 0.075mg/g 3PO administered via intraperitoneal injection suppresses tumor growth in two transgenic mouse models of breast cancer (MMTV-H-ras: 30% inhibition; MMTV-Erbb2(Her2/neu): 60% inhibition). Interestingly, the Her2 positive cell lines (SK-BR-3, BT-549) and the Her2 mouse transgenic model were more susceptible to PFKFB3 inhibition suggesting that the Her2 phenotype may be more sensitive to disruption of glycolytic flux. Taken together, these data support the clinical development of 3PO and other PFKFB3 inhibitors as chemotherapeutic agents against breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3064.