B78
Effects of phenformin on establishment and growth of MCF7 tumour xenografts
Virginia Appleyard, Karen Murray, Dario Alessi, Stephan Wullschleger, Alastair Thompson
University of Dundee, UK
Background
The 5'AMP-activated protein kinase (AMPK) is an enzyme with functional orthologues conserved from yeast to humans which play a crucial role in cellular energy homeostasis. The potential of AMPK activators such as metformin and phenformin as anticancer agents by triggering a physiological signalling pathway that inhibits cell growth has been previously demonstrated in vitro and in epidemiological studies. In the present study we investigated the role of phenformin in the growth and establishment of tumour xenografts derived from MCF7 breast cancer cells which are oestrogen receptor positive and bear functional AMPK. MCF7 cells also carry an amplification of the chromosomal region containing the RPS6KB1 gene encoding for the S6K protein, leading to constitutively phosphorylation of mTOR.
Method
Nude mice with oestrogen pellet supplementation were divided into three groups: (1) drinking water replaced with 5% sucrose containing phenformin (300mg/kg) for at least 2 weeks prior to MCF7 cell injection; (2) established MCF7 xenograft tumours treated with phenformin (300mg/kg) in 5% sucrose; (3) untreated controls. After 28 days tumours, liver and spleen were harvested for further analysis.
Results
There were no signs of phenformin toxicity in the treated or pre-treated groups. Statistically significant inhibition in tumour growth rate of 80% was identified for pre-treated and treated mice (Students t-Test p < 0.05) compared with the control groups. AMPK activation was detected in the liver and spleen of pre-treated and treated mice using western blots. Slides prepared from pre-treated or treated tumours did not show differences in AMPK-α activation compared to untreated tumours, however, differences in AMPK pathway staining were identified including S6K.
Conclusion
Phenformin significantly inhibits the establishment and growth of MCF7 tumour xenografts with anticancer activity potentially mediated via the liver and spleen with involvement of the AMPK pathway.
