T9

Abstract

Background

Metformin is a antidiabetic drug with anticancer properties. However, the mechanism action by which metformin affects various cancer cells still unknown. It is known that tumor growth is accompanied by changes in the metabolic cascade that includes overproduction of lactate and adenosine. The adenosine is released into the extracellular environment and regulates differentiation, proliferation, and angiogenesis of tumor mass. We found that lactate is activator of key enzyme of adenosine metabolism – adenosine deaminase (ADA).

Aim

The aim of our study was to investigate the catabolism of adenosine in the tumor while taking metformin.

Materials and methods

In this study we investigated the level of adenosine, inosine, hypoxanthine and ADA activity in 15 women aged 46–76 years, with breast cancer (BC) T2-4N1M0 (cancer tissues) during treatment with metformin, 1000 mg per day for 3 months. Control group – 15 women aged 46–76 years, with stage T2-4N1M0 breast cancer (cancer tissues) without metformin therapy.

Statistical analysis was performed using the license package StatSoft. Statistica 12.0.

Results

ADA activity during treatment with metformin was 2-fold increased: 12.1 ± 2.49 nmol/min*mg in comparison with 4.77 ± 0.943 nmol/min*mg. Concentration of catabolic products of adenosine degradation was increased before metformin therapy. Inosine level was 0.121 ± 0.041 micro mol/g tissue (BC tissues from women without metformin 0.042 ± 0.015 micro mol/g tissue). Hypoxanthine 2.45 ± 0.428 micro mol/g tissue (in comparison with 0.711 ± 0.269 micro mol/g tissue). Whereas, adenosine level in BC after metformin therapy was 0.226 ± 0.148 micro mol/g tissue (in comparison with 0.186 ± 0.056 micro mol/g tissue), that were not significantly different.

Conclusion

Thus, we have found that metformin significantly increases the rate of catabolism of adenosine, and this in turn reduces the inhibitory effect on the tumor microenvironment cytotoxic cells. Therefore, our data for the first time provide novel evidence for a mechanism that the anticancer activities of metformin are due to adenosine metabolism regulation.