Antitumorigenic effect of memantine via interfering glutamate metabolism in mouse 4T1 breast tumor model

Albayrak G., Korkmaz F. D., Bali E. B., Bağrıaçık E. Ü.

Anti-Cancer Agents In Medicinal Chemistry, vol.21, pp.1-6, 2021 (SCI-Expanded)

  • Publication Type: Article / Article
  • Volume: 21
  • Publication Date: 2021
  • Journal Name: Anti-Cancer Agents In Medicinal Chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Biotechnology Research Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE
  • Page Numbers: pp.1-6
  • Gazi University Affiliated: Yes


Abstract: 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

for memantine.

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.