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Metformin: analysis of the molecular mechanisms associated with antiproliferative, cytotoxic, antimetastatic and MDR-reversing actvities in tumor cells


Although significative progress has been done to understand the molecular and functional biology of cancer cells, the treatment of the disease still presents inefficacious for the majority of the cases. Many factors contribute for this scenario such as: lack of selective action by the chemotherapic agents; emergence of multidrug resistance (MDR) cells, before or after the treatment, and the occurrence of tumor metastasis which is the cause of about 90% of death by carcinomas. Recent works have been showed that metformin, a generic glucose lowering drug used in the treatment of type 2 diabetes for more than 30 years, has the ability to inhibit the tumor proliferation and can induce cancer cell death. In addition, metformin also presents various other desirable antitumor properties such as low toxicity toward non tumor cells and ability to induce programmed cell death in cancer stem cells indicating that this hypoglycemic drug can act selectively against cancer cells and avoid recurrence of the disease, respectively. Studies done by our group also have been showed that metformin is efficient in the selective elimination of tumor cells of diverse origins including those derived of hepatic carcinoma and MDR cells of chronic myeloid leukemia. Indeed, our results demonstrated that the treatment of cells with metformin can induce a decrease in expression of P-glycoprotein, an efflux membrane transporter responsible for limiting cellular uptake of chemotherapics by cancer cells. Additionally, our studies showed that metformin can reduce the activity of matrix metalloproteinases, whose activities is essential during the metastatic process. Interestingly, we have been showing that all these effects of metformin are pronounced when cells are exposed to environmental with reduced availability of glucose. These results suggest the potential use of treatments which are based in the association of metformin to inhibitors of glucose uptake and/or modulators of glycolytic metabolism. The aim of the present project is to analyse the molecular mechanisms associated with the antiproliferative, cytotoxic and MDR reversing activity of metformin in the human chronic myeloid leukemic cell line K562 and its MDR phenotypic counterpart, Lucena. In addition, we aim to evaluate the ability of metformin to modulate the metastatic potential of these cells through effects in adhesion, invasion and migration potentials. (AU)

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