Phenformin as prophylaxis and therapy in breast cancer xenografts

• Published in: British journal of cancer Vol. 106; no. 6; pp. 1117 - 1122
• Main Authors: Appleyard, M V C L, Murray, K E, Coates, P J, Wullschleger, S, Bray, S E, Kernohan, N M, Fleming, S, Alessi, D R, Thompson, A M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.03.2012; Nature Publishing Group
• Subjects: 631/67/1059; 631/67/1347; 631/92/609; Adenylate Kinase - metabolism; Animals; Anticarcinogenic Agents - pharmacology; Anticarcinogenic Agents - therapeutic use; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - prevention & control; Cancer Research; Cell Line, Tumor; Drug Resistance; Enzyme Activation; Epidemiology; Female; Gynecology. Andrology. Obstetrics; Histones - metabolism; Humans; Ki-67 Antigen - metabolism; Liver - enzymology; Mammary gland diseases; Medical sciences; Metformin - pharmacology; Metformin - therapeutic use; Mice; Mice, Nude; Molecular Medicine; Oncology; Phenformin - pharmacology; Phenformin - therapeutic use; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - metabolism; Spleen - enzymology; Translational Therapeutics; Tumor Burden - drug effects; Tumors; Xenograft Model Antitumor Assays; phenformin; breast cancer; metformin; xenografts; therapy; Breast disease; Transplantation; Breast cancer; Malignant tumor; Heterotransplantation; Phenformin; Prevention; Mammary gland diseases; Biguanides; Cancerology; Treatment; Surgery; Animal; Graft; Metformin; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2012.56

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.