Glycolytic enzyme inhibitors in cancer treatment.
BACKGROUND
The radio- and chemotherapeutics currently used for the treatment of cancer are widely known to be characterized by a low therapeutic index. An interesting approach to overcoming some of the limits of these techniques is the exploitation of the so-called Warburg effect, which typically characterizes neoplastic cells. Interestingly, this feature has already been utilized with good results, but only for diagnostic purposes (PET and SPECT). From a pharmacological point of view, drugs able to perturb cancer cell metabolism, specifically at the level of glycolysis, may display interesting therapeutic activities in cancer.


OBJECTIVE
The pharmacological actions of these glycolytic enzyme inhibitors, based primarily on ATP depletion, could include: i) amelioration of drug selectivity by exploiting the particular glycolysis addiction of cancer cell; ii) inhibition of energetic and anabolic processes; iii) reduction of hypoxia-linked cancer-cell resistance; iv) reduction of ATP-dependent multi-drug resistance; and v) cytotoxic synergism with conventional cancer treatments.


CONCLUSIONS
Several glycolytic inhibitors are currently in preclinical and clinical development. Their clinical value as anticancer agents, above all in terms of therapeutic index, strictly depends on a careful reevaluation of the pathophyiological role of the unique metabolism of cancer cells in general and of Warburg effect in particular.
Scatena
Roberto
R
Catholic University, Department of Laboratory Medicine, Largo A. Gemelli 8, 00168 Rome, Italy. r.scatena@rm.unicatt.it
Bottoni
Patrizia
P
Pontoglio
Alessandro
A
Mastrototaro
Lucia
L
Giardina
Bruno
B
D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005634:Fructose-Bisphosphate Aldolase / Q000037:antagonists & inhibitors; D005956:Glucose-6-Phosphate Isomerase / Q000037:antagonists & inhibitors; D006019:Glycolysis / Q000187:drug effects*; D006593:Hexokinase / Q000037:antagonists & inhibitors; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy*; D010732:Phosphofructokinase-1 / Q000037:antagonists & inhibitors; D010736:Phosphoglycerate Mutase / Q000037:antagonists & inhibitors; D010751:Phosphopyruvate Hydratase / Q000037:antagonists & inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors; D014305:Triose-Phosphate Isomerase / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D007770:L-Lactate Dehydrogenase; D006593:Hexokinase; D010732:Phosphofructokinase-1; D011770:Pyruvate Kinase; C055686:glyceraldehyde 3-phosphate phosphatase; D010744:Phosphoric Monoester Hydrolases; D005634:Fructose-Bisphosphate Aldolase; D010751:Phosphopyruvate Hydratase; D014305:Triose-Phosphate Isomerase; D005956:Glucose-6-Phosphate Isomerase; D010736:Phosphoglycerate Mutase