Phenformin as prophylaxis and therapy in breast cancer xenografts

Abstract

Background:Observations that diabetics treated with biguanide drugs have a reduced risk of developing cancer have prompted an enthusiasm for these agents as anti-cancer therapies. We sought to determine the efficacy of the biguanide phenformin in the chemoprophylaxis and in the treatment of oestrogen receptor (ER)-positive MCF7 and receptor triple-negative MDAMB231 xenografts in immunocompromised mice. We also compared the efficacy of phenformin and metformin in the treatment of MDAMB231.Methods:Immunocompromised mice were divided into groups: (1) phenformin administered for 2 weeks prior to cell injection; (2) established tumours treated with phenformin; (3) established tumours treated with metformin (only for MDAMB231 tumours); (4) untreated controls. Post-treatment tumours, liver and spleen were harvested for further analysis.Results:Phenformin significantly inhibited both the development and growth of MCF7 and MDAMB231 tumours, and for MDAMB231 at greater efficacy than metformin without murine toxicity. The number of mitotic figures was significantly fewer in xenografts treated with phenformin compared with controls. Results suggested that the mechanism of action of phenformin in vivo is consistent with AMPK activation.Conclusion:Phenformin has clinical potential as an antineoplastic agent and should be considered for clinical trials both in ER-positive and triple-negative breast cancer.

Carbon Source and Myc Expression Influence the Antiproliferative Actions of Metformin

“…This, in turn, reduces the hyperglycemia of type II diabetes, with secondary reduction in the hyperinsulinemia seen in this condition (15). These systemic actions may contribute to the antineoplastic effects of metformin seen in some in vivo models (10,16). Cell autonomous actions, such as those described in this paper, may also play critical roles in antineoplastic actions of biguanides, provided adequate drug concentrations are achieved in vivo.…”

Phenformin Activates the Unfolded Protein Response in an AMP-activated Protein Kinase (AMPK)-dependent Manner

“…Phenformin has recently attracted interest because of its greater antitumor efficacy compared with metformin in mouse models (50). The enhanced cell cycle inhibitor p21 has been suggested as one of the mechanisms underlying the inhibition of cell proliferation and induction of apoptosis in phenformintreated cancer cells (51).…”

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

“…An important point to bear in mind is that effects of metformin are unlikely to be homogeneous across tissues, not only due to higher concentration in the portal circulation than the systemic circulation following oral dosing, but also due to the fact that tissues vary in their expression of the transport molecules required for metformin uptake. Although these transporters play a key role for metformin uptake at drug concentrations achievable in vivo , cellular accumulation of other more lipophilic biguanides, such as phenformin, are less dependent on active transport, and therefore may differ greatly from metformin in terms of tissue distribution and have greater antineoplastic activity, as suggested by laboratory studies (75)(76)(77).…”

“…Phenformin is associated with higher risk of lactic acidosis than metformin, but nevertheless has a better safety profi le than most antineoplastic agents in current use, and is more effective than metformin in preclinical models, probably because of its pharmacokinetic characteristics (75)(76)(77). There are libraries of many biguanides that could be screened for antineoplastic activity and/or used as lead compounds for optimization of pharmacokinetics.…”