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Research Articles: Therapeutics, Targets, and Development

Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth

Departments of ¹ Medicine and ² Biochemistry and Molecular Biology and ³ Molecular Targets Group, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky

Requests for reprints: Jason Chesney, Room 204E, Delia Baxter II Building, 580 South Preston Street, Louisville, KY 40202. Phone: 502-852-3679. E-mail: jason.chesney{at}louisville.edu

Abstract

6-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 herein the computational identification of a small-molecule inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), which suppresses glycolytic flux and is cytostatic to neoplastic cells. 3PO inhibits recombinant PFKFB3 activity, suppresses glucose uptake, and decreases the intracellular concentration of Fru-2,6-BP, lactate, ATP, NAD⁺, and NADH. 3PO markedly attenuates the proliferation of several human malignant hematopoietic and adenocarcinoma cell lines (IC₅₀, 1.4-24 µmol/L) and is selectively cytostatic to ras-transformed human bronchial epithelial cells relative to normal human bronchial epithelial cells. The PFKFB3 enzyme is an essential molecular target of 3PO because transformed cells are rendered resistant to 3PO by ectopic expression of PFKFB3 and sensitive to 3PO by heterozygotic genomic deletion of PFKFB3. Importantly, i.p. administration of 3PO (0.07 mg/g) to tumor-bearing mice markedly reduces the intracellular concentration of Fru-2,6-BP, glucose uptake, and growth of established tumors in vivo. Taken together, these data support the clinical development of 3PO and other PFKFB3 inhibitors as chemotherapeutic agents. [Mol Cancer Ther 2008;7(1):110–20]

Grant support: Department of Defense Breast Cancer Research Program Postdoctoral Multidisciplinary Award BC051684 (B. Clem), Leukemia and Lymphoma Society Translational Research Grant (J. Chesney), NIH grant 1 R01 CA11642801 (J. Chesney), Philip Morris External Research Program (unrestricted; J. Chesney), and NIH grant 1P20 RR18733 (JC and J.O. Trent).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Received 7/18/07; revised 10/ 5/07; accepted 11/19/07.