Phenformin (BRN 1977317) is a biguanide compound with anticancer and anti-glycemic activity, inhibits skin tumor growth and promotes keratinocyte differentiation and apoptosis.

Phenformin acts by promoting phosphorylation and activation of AMPKalpha1 and AMPKalpha2 without altering the activity of the LKB1 gene [1]. In isolated hearts, Phenformin increased AMPK activity and phosphorylation levels, which correlated with increased AMPK activity and increased intracellular [AMP] [2].Phenformin was 50 times more potent than Metformin and was able to inhibit mitochondrial complex I. In LKB1-deficient non-small cell lung cancer cell lines, the Phenformin was able to induce apoptosis.Phenformin (2 mM) also induced AMPK signaling and increased levels of P-AMPK and P-Raptor.Phenformin induced higher levels of cellular stress, which in turn triggered the induction of P-Ser51 eIF2α and its downstream target CHOP, which are late stage molecular markers of apoptosis. In chronically treated KLluc mice, Phenformin induced survival and treatment response [3]. In H441 cells, Phenformin and AICAR increased AMPK activity in a dose-dependent manner, maximizing activation of the kinase at 5-10 mM and 2 mM concentrations. In H441 cell monolayers, Phenformin significantly reduced basal ion migration (measured as short-circuit current) by approximately 50%. Phenformin and AICAR significantly reduced amiloride-sensitive transmembrane Na ion transport compared to controls. Phenformin and AICAR inhibited amiloride-sensitive transmembrane Na ion transport in H441 cells by activating AMPK and inducing inhibition of sodium ion entry at the terminal and basolateral sides of ENaC cells via the Na+, K+ ATPase [4]. In rats treated with Phenformin, their blood insulin levels tend to decrease (radioimmunoassay) [5].