Phenformin HCl

Phenformin stimulates the phosphorylation and activation of AMPKalpha1 and AMPKalpha2 without altering LKB1 activity. ^[1] Phenformin increases AMPK activity and phosphorylation in the isolated heart, the increase in AMPK activity is always preceded by and correlated with increased cytosolic [AMP]. ^[2] Phenformin is a 50-fold more potent inhibitor of mitochondrial complex I than 1,1-Dimethylbiguanide. Phenformin robustly induces apoptosis in LKB1 deficient NSCLC cell lines. Phenformin at 2 mM similarly induces AMPK signaling as shown by increased P-AMPK and P-Raptor levels. Phenformin induces higher levels of cellular stress, triggering induction of P-Ser51 eIF2α and its downstream target CHOP, and markers of apoptosis at later times. Phenformin induces a significant increase in survival and therapeutic response in KLluc mice following long-term treatment. ^[3] Phenformin and AICAR increases AMPK activity in H441 cells in a dose-dependent fashion, stimulating the kinase maximally at 5-10 mm and 2 mm, respectively. Phenformin significantly decreases basal ion transport (measured as short circuit current) across H441 monolayers by approximately 50% compared with that of controls. Phenformin and AICAR significantly reduce MK-870-sensitive transepithelial Na+ transport compared with controls. Phenformin and AICAR suppress MK-870-sensitive Na+ transport across H441 cells via a pathway that includes activation of AMPK and inhibition of both apical Na+ entry through ENaC and basolateral Na+ extrusion via the Na+,K+-ATPase. ^[4] Phenformin-treated rats reveals a tendency towards a decrease in blood insulin level (radioimmunoassay). ^[5]

Phenformin also increases levels of P-eIF2α and its target BiP/Grp78 in normal lung as well as in lung tumors of mice. ^[3]