Phenformin (hydrochloride)

Phenformin (hydrochloride) is a hydrochloride salt of phenformin that is an anti-diabetic drug from the biguanide class, can activate AMPK activity.

Signaling Pathways >> Epigenetics >> AMPK

Signaling Pathways >> PI3K/Akt/mTOR >> AMPK

Research Areas >> Cancer

AMPK

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 metformin. 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 amiloride-sensitive transepithelial Na+ transport compared with controls. Phenformin and AICAR suppress amiloride-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 increases levels of P-eIF2α and its target BiP/Grp78 in normal lung as well as in lung tumors of mice[3].

Total AMPK activity is measured using the method of Dagher et al. AMPK activity is quantified in the resuspended pellet as incorporation of 32P from [γ-32P]ATP (10 GBq/mmol) into a synthetic peptide with the specific target sequence for AMPK, the SAMS peptide. Radioactivity is measured using a liquid scintillation counter. Protein content in the solution containing the resupended (NH4)2SO4 pellet is determined using the Bradford method.

[1]. Sakamoto K, et al. Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. Am J Physiol Endocrinol Metab.?2004 Aug;287(2):E310-7.

[2]. Zhang L, et al. Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H457-66.

[3]. Moreira AL, et al. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med. 1993 Jun 1;177(6):1675-80.

[4]. Woollhead AM, et al. Phenformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) activation of AMP-activated protein kinase inhibits transepithelial Na+ transport across H441 lung cells. J Physiol. 2005 Aug 1;566(Pt 3):781-92. Epub 2005

[5]. Dilman VM, et al. Inhibition of DMBA-induced carcinogenesis by phenformin in the mammary gland of rats. Arch Geschwulstforsch. 1978;48(1):1-8.

Dorsomorphin dihydrochloride | Acadesine (AICAR) | A-769662 | Bempedoic Acid | Flufenamic Acid | WZ 4003 | PF 06409577 | Dantron | O-304 | 6-Gingerol | 7-Methoxyisoflavone | HTH 01-015 | YLF-466D | Ampkinone

MOLECULAR FORMULA :

C10-H15-N5.Cl-H

MOLECULAR WEIGHT :

241.76

WISWESSER LINE NOTATION :

MUYZMYUM&M2R &GH

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

938 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

140 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

17500 ug/kg

TOXIC EFFECTS :

Behavioral - convulsions or effect on seizure threshold Lungs, Thorax, or Respiration - cyanosis Lungs, Thorax, or Respiration - respiratory depression

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

407 mg/kg

TOXIC EFFECTS :

Endocrine - hypoglycemia

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

150 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

200 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

17800 ug/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - guinea pig

DOSE/DURATION :

47 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - guinea pig

DOSE/DURATION :

19 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

MUTATION DATA

TYPE OF TEST :

DNA damage

TEST SYSTEM :

Rodent - rat Liver

DOSE/DURATION :

1 mmol/L

REFERENCE :

EMMUEG Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- Volume(issue)/page/year: 24,181,1994