Mechanistic Basis for Use of Aldose Reductase Inhibitors to Treat Breast Cancer

Abstract

Abstract : Changes in glucose metabolism during diabetes are linked to an increased risk for the development of breast cancer. Aldose reductase, the rate-limiting polyol pathway enzyme that converts glucose into sorbitol, not only is an important mediator of the pathologies associated with diabetes, but is also upregulated in many cancer cells and may be involved in cancer cell resistance to chemotherapeutic drugs. Furthermore, increased expression of aldose reductase in cancer cells may reduce the effectiveness of chemotherapeutic compounds by increasing drug metabolism or by decreasing drug uptake. Thus, these studies addressed the hypothesis that inhibition of aldose reductase enhances cell sensitivity to anti-cancer drugs. Using the specific aldose reductase inhibitor, ethyl 1 -benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate (EBPC), experiments tested whether aldose reductase inhibition could enhance the cytotoxic effects of the anti-cancer agents doxombicin or cisplatin in Hela cervical carcinoma and MDA-MB-468 breast cancer cells. Cell growth and death assays revealed that co-administration of aldose reductase inhibitors increased the cytotoxic effects of chemotherapeutic drugs on cervical and breast cancer cells. In summary, these data provide evidence to support further studies testing the use of aldose reductase inhibitors as adjuvant therapy to improve the effectiveness of existing chemotherapeutic drugs.