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

Molecular Cancer Therapeutics
Brian ClemJason Chesney

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 micromol/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 ge...Continue Reading

References

May 1, 1991·Archives of Biochemistry and Biophysics·H K KoleE Racker
Jan 1, 1987·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·A HennipmanG E Staal
Jun 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·E RackerR Feldman
Jun 1, 1981·Proceedings of the National Academy of Sciences of the United States of America·E Van SchaftingenH G Hers
Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Mar 21, 1998·Proceedings of the National Academy of Sciences of the United States of America·H ShimC V Dang
Mar 17, 1999·Proceedings of the National Academy of Sciences of the United States of America·J ChesneyR Bucala
Dec 2, 1999·Experimental Cell Research·C V DangK Zeller
May 24, 2000·The Journal of Biological Chemistry·R C OsthusC V Dang
May 2, 2001·Biochemistry·H LiuT J Lampidis
Jun 26, 2003·Nucleic Acids Research·Ramu ChennaJulie D Thompson
Feb 24, 1956·Science·O WARBURG
Jan 26, 2005·Toxicology and Applied Pharmacology·Rishi Raj ChhipaManoj Kumar Bhat
Mar 1, 2005·Proceedings of the National Academy of Sciences of the United States of America·Buddhadeb DawnRoberto Bolli
Apr 21, 2005·Proceedings of the National Academy of Sciences of the United States of America·Arvind RamanathanStuart L Schreiber
Oct 15, 2005·Clinical Radiology·K WechalekarG Cook
Aug 17, 2006·Current Opinion in Clinical Nutrition and Metabolic Care·Jason Chesney

❮ Previous
Next ❯

Citations

Feb 9, 2011·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Chi V DangPing Gao
Oct 29, 2011·Pharmaceutical Research·Shanjida AkterYounsoo Bae
Jul 25, 2009·Nature Reviews. Cancer·David B Shackelford, Reuben J Shaw
Jan 29, 2013·Oncogene·M R ReynoldsB F Clem
Mar 15, 2013·Journal of the National Cancer Institute·Annalisa PacilliLorenzo Montanaro
Sep 2, 2010·American Journal of Clinical Oncology·Brijesh M MadhokDavid G Jayne
Sep 27, 2012·Cancer Discovery·Jason R Cantor, David M Sabatini
Jun 3, 2011·The Journal of Clinical Investigation·Lauren L C MarottaKornelia Polyak
Dec 5, 2013·Molecular Cancer·Shanmugasundaram Ganapathy-Kanniappan, Jean-Francois H Geschwind
May 18, 2012·Journal of Translational Medicine·Sucheta TelangJason Chesney
Dec 3, 2010·PloS One·Aleksandra Usenik, Matic Legiša
Jun 10, 2014·PloS One·Bhanu Chandra MulukutlaWei-Shou Hu
Jun 10, 2010·Future Oncology·Ralph J DeBerardinis
Jan 24, 2014·Cancer & Metabolism·Alden C KlarerSucheta Telang
Jun 8, 2014·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Zhe-Yu HuYa Cao
Jun 10, 2014·Critical Reviews in Oncology/hematology·Nada Al HasawiYunus A Luqmani
Jan 13, 2015·Future Medicinal Chemistry·Igor Marín de MasMarta Cascante
Nov 15, 2014·Breast Cancer Research and Treatment·S N OnonyeL Pusztai
Aug 2, 2011·Chinese Journal of Cancer·Naima HammoudiPeng Huang
Feb 22, 2012·Expert Opinion on Therapeutic Targets·Mamatha M ReddyMartin Sattler
Oct 11, 2015·Seminars in Cancer Biology·Matthew D HirscheyUNKNOWN Target Validation Team
Sep 24, 2008·Expert Opinion on Investigational Drugs·Roberto ScatenaBruno Giardina
Apr 26, 2014·Expert Opinion on Biological Therapy·Meghna TalekarMansoor Amiji
Nov 20, 2012·Pharmacology & Therapeutics·Mohita UpadhyayPerumal Vivekanandan
Dec 31, 2011·Drug Discovery Today·Neil P Jones, Almut Schulze
Jan 4, 2012·Pharmacology & Therapeutics·Teresa W-M FanAndrew N Lane
Jan 12, 2016·Trends in Cell Biology·Giulia SantinonSirio Dupont
Aug 10, 2010·Trends in Biotechnology·Bhanu Chandra MulukutlaWei-Shou Hu
May 9, 2009·Drug Discovery Today·Claudio N Cavasotto, Sharangdhar S Phatak
May 21, 2009·Experimental and Molecular Pathology·Abdullah YalcinJason Chesney
May 21, 2009·Experimental and Molecular Pathology·Andrew N LaneDonald M Miller
May 21, 2009·Experimental and Molecular Pathology·Magdalena M DaileyJohn O Trent
Mar 15, 2016·Cancer Treatment Reviews·Francesco MassariRodolfo Montironi
Jul 29, 2011·Annals of the New York Academy of Sciences·Dong Hoon SuhYong Sang Song
May 14, 2011·The FEBS Journal·Anique HerlingHermann-Georg Holzhütter
Sep 8, 2010·Cell Biochemistry and Function·Mei-Yin SuJia-Ming Chang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Metabolic Reprogramming (Keystone)

Cancer metabolic reprogramming is important for the rapid growth and proliferation of cancer cells. Cancer cells have the ability to change their metabolic demands depending on their environment, regulated by the activation of oncogenes or loss of tumor suppressor genes. Here is the latest research on cancer metabolic reprogramming.

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.

Cancer Metabolic Reprogramming

Cancer metabolic reprogramming is important for the rapid growth and proliferation of cancer cells. Cancer cells have the ability to change their metabolic demands depending on their environment, regulated by the activation of oncogenes or loss of tumor suppressor genes. Here is the latest research on cancer metabolic reprogramming.