Mechanism of action of lonidamine in the 9L brain tumor model involves inhibition of lactate efflux and intracellular acidification

摘要: Malignant gliomas have been associated with a high rate of glycolytic activity which is believed necessary to sustain cellular function and integrity. Since lonidamine (LND) reduce tumor glucose utilization by inhibition the mitochondrially-bound enzyme hexokinase (HK), 31P magnetic resonance spectroscopy (MRS) was used noninvasively follow effects LND on both pH high-energy phosphate metabolites; ATP, phosphocreatine (PCr) inorganic (Pi) in subcutaneous rat 9L gliosarcomas. spectra acquired 5 min intervals pre- post administration 50 100 mg/kg, i.p. revealed an acidotic shift − 0.25 0.45 units, respectively within 30 administration. The ATP/Pi ratio tumors decreased 40% control Pi levels increased 280% over 3 hr period. exerted no effect blood flow mean arterial pressure. Brain muscle metabolite were also unaffected LND. In vitro measurements cultured cell intra- extracellular lactate, pentose pathway (PPP) (HK) activities suggest that mode action involves lactate efflux intracellular acidification. selective reduction energy metabolites may be exploitable for sensitizing radiation, chemotherapy or hyperthermia.