title: Inhibition of Growth by Combined Treatment with Inhibitors of Lactate Dehydrogenase and either Phenformin or Inhibitors of 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase 3.
abstract: Enhanced glycolysis in cancer cells presents a target for chemotherapy. Previous studies have indicated that proliferation of cancer cells can be inhibited by treatment with phenformin and with an inhibitor of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB) namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). In the present work, the action of two inhibitors that are effective at lower concentrations than 3PO, namely 1-(3-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PQP) and 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15) were investigated. The inhibitors of lactate dehydrogenase (LDHA) studied in order of half-maximal inhibitory concentrations were methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (NHI-2) < isosafrole < oxamate. In colonic and bladder cancer cells, additive growth inhibitory effects were seen with the LDHA inhibitors, of which NHI-2 was effective at the lowest concentrations. Growth inhibition was generally greater with PFK15 than with PQP. The increased acidification of the culture medium and glucose uptake caused by phenformin was blocked by combined treatment with PFKFB3 or LDHA inhibitors. The results suggest that combined treatment with phenformin and inhibitors of glycolysis can cause additive inhibition of cell proliferation and may mitigate lactic acidosis caused by phenformin when used as a single agent.
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, U.S.A. lea@njms.rutgers.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lea
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, U.S.A.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Guzman
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, U.S.A. Department of Biology, Medgar Evers College - City University of New York, Brooklyn, NY, U.S.A.
authors.forename: Charles
authors.initials: C
authors.lastname: Desbordes
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors*; D010629:Phenformin / Q000494:pharmacology*; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D011725:Pyridines; D010629:Phenformin; D007770:L-Lactate Dehydrogenase; D025481:Phosphofructokinase-2; D005947:Glucose
keywords: Bladder cancer; PFKFB3 inhibitor; colon; glycolysis; growth; lactate dehydrogenase; phenformin