Various biguanide derivatives are used as antihyperglycemic and antimalarial drugs (e.g., 1,1-dimethyl biguanide (metformin), phenylethyl biguanide (phenformin), N-(4-chlorophenyl)-N'-(isopropyl)-imidodicarbonimidic diamide (proguanil)); however, no common mechanism has been suggested in these controversial therapeutic actions. Biguanides bind endogenous metals that inhibit cysteine proteases i...

MEK inhibition is potentially valuable in targeting KRAS-mutant non-small cell lung cancer (NSCLC). Here, we analyzed whether concomitant LKB1 mutation alters sensitivity to the MEK inhibitor selumetinib, and whether the metabolism drug phenformin can enhance the therapeutic effect of selumetinib in isogenic cell lines with different LKB1 status. Isogenic pairs of KRAS-mutant NSCLC cell lines A...

Activation of unfolded protein response (UPR) is associated with the disruption of endoplasmic reticulum (ER) homeostasis and has been implicated in the pathogenesis of many human metabolic diseases, including obesity and type-2 diabetes. However, the nature of the signals activating UPR under these conditions remains largely unknown. Using a method that we recently optimized to directly measur...

Thirty-eight patients who presented with diabetes and a changed state of consciousness satisfied the criteria for lactic acidosis. Sixteen patients were non-ketotic, and 15 of these were receiving phenformin on admission. In all but one of these 15 patients, however, additional renal or cardiovascular abnormalities, or both, could be identified, which supported a multifactorial aetiology for la...

Two cases with clinical signs ofpulmonary hypertension and right heart failure developing during phenformin treatment are reported. The patients were clinically improved on withdrawal of phenformin. Two possible explanations for the pulmonary hypertension were considered: cellular anaerobiosis or alphareceptor stimulation of the pulmonary vessels. The 4 patients sofar reported direct attention ...

In this study, we focused on an analysis of biguanides effects on mitochondrial enzyme activities, mitochondrial membrane potential and membrane permeability transition pore function. We used phenformin, which is more efficient than metformin, and evaluated its effect on rat liver mitochondria and isolated hepatocytes. In contrast to previously published data, we found that phenformin, after a ...

Abstract Diffuse Midline Gliomas (DMG) is the leading cause of brain tumor-related death in children. Currently, radiation only treatment that offers transient benefit but almost all DMG relapse due to radioresistance. Compared normal tissue, are hypo-perfused with tumor cells being exposed hypoxia, a low oxygen microenvironment serves as potent barrier effective radiotherapy. Biguanides hypogl...

The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ∼20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and a...

Secretory Phospholipase A2 of type IIA (sPLA2 IIA) plays a crucial role in the production of lipid mediators by amplifying the neointimal inflammatory context of the vascular smooth muscle cells (VSMCs), especially during atherogenesis. Phenformin, a biguanide family member, by its anti-inflammatory properties presents potential for promoting beneficial effects upon vascular cells, however its ...