Clotrimazole Preferentially Inhibits Human Breast Cancer Cell Proliferation, Viability and Glycolysis

Abstract

BackgroundClotrimazole is an azole derivative with promising anti-cancer effects. This drug interferes with the activity of glycolytic enzymes altering their cellular distribution and inhibiting their activities. The aim of the present study was to analyze the effects of clotrimazole on the growth pattern of breast cancer cells correlating with their metabolic profiles.Methodology/Principal FindingsThree cell lines derived from human breast tissue (MCF10A, MCF-7 and MDA-MB-231) that present increasingly aggressive profiles were used. Clotrimazole induces a dose-dependent decrease in glucose uptake in all three cell lines, with Ki values of 114.3±11.7, 77.1±7.8 and 37.8±4.2 µM for MCF10A, MCF-7 and MDA-MB-231, respectively. Furthermore, the drug also decreases intracellular ATP content and inhibits the major glycolytic enzymes, hexokinase, phosphofructokinase-1 and pyruvate kinase, especially in the highly metastatic cell line, MDA-MB-231. In this last cell lineage, clotrimazole attenuates the robust migratory response, an effect that is progressively attenuated in MCF-7 and MCF10A, respectively. Moreover, clotrimazole reduces the viability of breast cancer cells, which is more pronounced on MDA-MB-231.Conclusions/SignificanceClotrimazole presents deleterious effects on two human breast cancer cell lines metabolism, growth and migration, where the most aggressive cell line is more affected by the drug. Moreover, clotrimazole presents little or no effect on a non-tumor human breast cell line. These results suggest, at least for these three cell lines studied, that the more aggressive the cell is the more effective clotrimazole is.

Sirtuin-3 modulates Bak- and Bax-dependent apoptosis

“…Cells of the breast cancer cell line, MDA-MB-231, also express a high level of hexokinase II (Furtado et al, 2012;Zancan et al, 2010). As shown in (Fig.…”

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

“…The association of glycolytic enzymes to these intracellular ultrastructures is an important mechanism of regulation of glucose consumption, determining if it will be completely oxidized, fermented, or used as carbon source for biosynthesis (17,19,20,22,36,(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53). The more associated the enzymes are, the less oxidized glucose is, being preferentially fermented and used to biosynthesis.…”

Pantoprazole inhibits human gastric adenocarcinoma SGC-7901 cells by downregulating the expression of pyruvate kinase M2

“…The SGC-7901 cells were seeded in 100 µl of medium per well, at a density of 1x10 4 /well, in 96-well plates and treated with 5 mg/ml PPZ for 24 h. The cytotoxicity of PPZ was assessed by a cell counting kit-8 assay (KeyGen Biotech Co., Ltd., Nanjing, Jiangsu, China), according to the manufacturer's protocol. The cytotoxicity was expressed as the relative cell viability, using the following formula: Cell viability (%) = (OD of drug-treated sample / OD of untreated sample) x 100.…”

“…In another study, aerobic glycolysis was an essential step that ultimately resulted in tumorigenesis, which was characterized by enhanced activity of glycolytic enzymes and distinct changes in the glycolytic isoenzyme (3). There were three rate-limiting enzymes of glycolysis, consisting of hexokinase, phosphofructokinase and pyruvate kinase (4). Among these enzymes, pyruvate kinase catalyzed the final step of glycolysis, which is associated with the production of adenosine triphosphate and pyruvate, and was important during the process of glycolysis (5).…”