ABSTRACT
The action of lonidamine, 1,(2,4 dichlorobenzyl)-1H-indazol-3-carboxylic acid, on protein synthesis of neoplastic cells growing both in vivo and in vitro has been investigated. Lonidamine decreases amino acid incorporation in all cells tested, although the inhibition is partially relieved by glucose. The inhibition of labeled precursors into acid-insoluble material cannot be ascribed to an impairment of amino acid uptake which, on the contrary, is enhanced by the drug. Tests on cell-free systems showed that lonidamine does not inhibit the tobacco mosaic virus (TMV)-mRNA-directed in vitro protein synthesis, thus indicating that protein synthetic machinery per se is not affected. The inhibition of the rate of protein synthesis achieved by lonidamine must be ascribed to an effect on energy-yielding processes with a mechanism similar to that observed in other metabolic inhibitors. Lonidamine, however, because of its capacity to inhibit both respiration and glycolysis in neoplastic cells, is effective at 10 to 20 times lower concentrations. DNP and oligomycin potentiate the inhibitory effect of lonidamine on the rate of protein synthesis. This finding substantiates the idea that neoplastic cells, including those growing in ascitic form, utilize mitochondrial oxidative phosphorylation as the main source of ATP for their biosynthetic processes.
Subject(s)
Antineoplastic Agents/pharmacology , Indazoles/pharmacology , Neoplasm Proteins/biosynthesis , Pyrazoles/pharmacology , Amino Acids/metabolism , Animals , Carcinoma, Ehrlich Tumor/metabolism , Cell Line , Cell-Free System , Dinitrobenzenes/pharmacology , Glycolysis/drug effects , Humans , Kinetics , Lactates/biosynthesis , Leukemia, Experimental/metabolism , Male , Melanoma/metabolism , Mice , Oligomycins/pharmacology , Rabbits , Sarcoma, Experimental/metabolismABSTRACT
The effect of lonidamine on oxygen consumption, aerobic lactate production, and [U-14C]glucose metabolism of rat Sertoli cells was investigated. The results may be summarized as follows: (1) Sertoli cells show well-developed energy metabolism both in vitro and in vivo. (2) The rate of aerobic lactate production is markedly higher than in other cell types, either normal differentiated or neoplastic, such as Ehrlich ascites tumor cells. (3) Lonidamine does not affect respiration and aerobic glycolysis of Sertoli cells. This finding is consistent with previous data which demonstrated that the antispermatogenic effect can be mainly ascribed to an irreversible alteration of germ cell mitochondria induced by 1-substituted indazole-3-carboxylic acids of which lonidamine represents one of the most potent derivatives. (4) The functional impairment induced by lonidamine on rat Sertoli cells cannot be ascribed to an action on the energy metabolism even if, up to date, the biochemical target is still unclear.
