Unfortunately, recent evidence suggests that the prolonged exposure of estrogen receptor (ER)-positive human breast cancer cells to metformin upregulates AKT/Snail1, suppresses ER and renders these cells tolerant to the toxicity of both metformin and tamoxifen; a phenomenon known as cross-resistance, irrespective of AMPK stimulation [67]. precious time from bench to bedside to aid the fight in the arena of cancer. and data or clinical data from studies in DM type II patients or nondiabetic individuals. Despite the fact that many anti-diabetic medications are currently available in the market, only the biguanide metformin and the thiazolidinedione (TZD) pioglitazone are mentioned. This is why insulin administered for the management of DM type I and insulin secretagogues (sulfonylureas) have been associated with an increased incidence of cancer [16,17,18]. Studies regarding the correlation (either positive or negative) among glucagon-like peptide 1 (GLP-1)-based medications including dipeptidyl peptidase 4 (DDP-4) inhibitors (the so-called gliptins) or anti-diabetics that target renal sodium-glucose cotransporter 2 (SGLT2 inhibitors or gliflozins) and cancer, cannot be considered as conclusive [19,20]. On the other hand, only little evidence has been provided for the anti-tumor properties of non-sulfonylurea secretagogues (known as glinides) or -glucosidase inhibitors [21,22] whereas the TZDs rosiglitazone and troglitazone that fall into the same category of drugs which exhibit profound anti-tumor activity [23,24,25,26,27] have been withdrawn from the market [28] due to their cardiotoxicity and hepatotoxicity, respectively. This is also the GNE0877 case for the biguanide phenformin that also exhibits anti-cancer properties [29,30,31], but is no longer commercially available because of its severe adverse lactic acidosis effect [32]. 2. Metformin and Pioglitazone: Overview of Current Clinical Use and Molecular Targets Metformin is a first-line anti-diabetic agent [33] widely prescribed all over the world. It acts as an insulin sensitizer and it can be used either as monotherapy or as part of combinational formulations. Metformin can also prevent the development of diabetes in subjects diagnosed with prediabetes [34]. However, the formal use of metformin is only for the treatment of diabetes. Pioglitazone is also used for the treatment of DM type II [35] and can be administered alone or in conjunction with other anti-diabetics including metformin GNE0877 or sulfonylurea analogues. There is convincing evidence for a direct correlation between DM type II (also called adult-onset or non-insulin-dependent DM) and cancer [36,37,38,39], particularly postmenopausal breast cancer [40,41]. Notably, patients with DM type II run a 10%C20% greater risk than non-diabetic females for developing breast cancer while up to 16% of breast cancer patients are diabetics [42]. In addition, DM type II is associated with worse Rabbit Polyclonal to MNT prognosis and poor outcome of breast cancer [43]. DM type II is a metabolic disorder characterized by the disturbed blood glucose control, insulin resistance and hyperinsulinemia [36]. The latter clinical finding, in turn, is linked with the pathogenesis of cancer due to the mitogenic activity of insulin [36,37,44]. Yet, recent evidence indicates that the anti-cancer properties of metformin are largely attributed GNE0877 to cell autonomous mechanisms [32]. Metformin acts as an activator of AMP-activated protein kinase (AMPK) which serves as a master metabolic sensor and is a negative modulator of the mammalian target of rapamycin (mTOR) [45]; a point of convergence for tumorigenesis and energy homeostasis [46]. AMPK and its upstream activator, the LKB1 tumor suppressor, are thought to play a central role in the anti-cancer function of metformin [47,48]. However, metformin can also stimulate AMPK-independent pathways which halt cancer cell proliferation [49, 50] or it may engage an AMPK-dependent/LKB1-independent pathway to suppress the proliferation of malignant cells [51]. To date, it has been suggested that the antiproliferative activity of.