Background: Repurposing drug is an efficient strategy as the drug discovery process is timeconsuming,
laborious and costly. Memantine is already used in Alzheimer’s disease to prevent neurons from
excess glutamate toxicity. As cancer cells benefit from higher amounts of cellular energetics like glucose and
glutamine, we used memantine to interfere with the glutamate metabolism in order to restrict cancer cells'
glutamine as a source for their growth.
Objective: To investigate the potential antitumor effect of memantine by reducing glutamate levels in 4T1 mouse
breast cancer model.
Methods: 24 Balb/c female mice were subcutaneously inoculated with 4T1 cells. When tumors were palpable,
memantine treatment was initiated as 5 and 10 mg/kg daily intraperitoneal injection. Tumor growth was recorded
every 2–3 days. Tumor volumes, serum glutamate levels, spleen IL-6 levels, genome-wide DNA methylation
levels and GSK3B. pGSK3B protein expressions were measured to enlighten the anticancer mechanism of action
Results: We found that both two doses (5 and 10mg/kg) decreased tumor growth rates and serum glutamate
levels significantly (p<0.05). 10mg/kg treatment increased spleen IL-6 levels (p<0.05) and decreased genomewide
DNA methylation levels. Memantine treatment decreased GSK3B protein expression levels in tumor tissue
Conclusion: To the best of our knowledge, this is the first study that investigates the antitumor activity of
memantine in a breast cancer tumor model. Our results suggest a potent anticancer mechanism of the action for
memantine. Memantine decreased genome wide methylation and serum glutamate levels that are associated with
a poor prognosis. Therefore, Memantine might be used for targeting glutamine metabolism in cancer treatment.