BACKGROUND:
While genetic testing for familial cancer has excelled, the
prevention options for those carrying high risk alleles have
not. Altered bioenergetics is now acknowledged as a hallmark
of cancer, and several very safe drugs are available
that can target this phentoype. Dichloroacetate (DCA)
inactivates pyruvate dehydrogenase kinase, resulting in
activation of pyruvate dehydrogenase, reduced lactic acid
production and increased mitochondrial activity. Metformin,
a type 2 diabetes treatment which activates AMPK,
thereby inhibiting mTOR, has unambiguously been
demonstrated to reduce the risk of many cancer types in
diabetics. We have tested these drugs as chemopreventive
agents against the mammary tumours that occur in the
BALB/c-Trp53+/- mouse spontaneous tumour model.
MATERIALS and METHODS
Breast cancer cell lines were examined for cell viability
after DCA and/or metformin treatment in vitro (neutral
red uptake assay). Four groups of female BALB/c-Trp53+/-
mice were given distilled water (n=75), DCA (1.5 g/L in
drinking water, ~180 mg/ kg/day, n=53), metformin (0.25
g/L in drinking water, ~30 mg/kg/day, n=61) or DCA
+metformin (n=51) from 8 weeks of age, and monitored
for tumour development over 78 weeks, and Kaplan-Meier
survival analysis was performed.
RESULTS
In vitro, DCA (1-5 mM) and metformin (30-300 uM),
alone or combined, significantly inhibited breast cancer
cell growth. In vivo, the overall tumour-free survival curves
for BALB/c-Trp53+/- mice were not significantly different between treatment groups, suggesting that metformin
does not reduce cancer risk in non-diabetics. However,
analysis of mammary tumours alone found that DCA
reduced the number and increased their latency (28.0% vs
20.8% of mice with mean latency of 55.0 vs 63.8 weeks,
untreated vs DCA respectively), whereas metformin had
no effect (26.2% of mice, mean latency 54.7 weeks). DCA
appeared to eliminate the early onset mammary tumours
(latency <52 weeks, p=0.02), while not affecting the occurrence
of longer latency tumours. In contrast, the two drug
combination had worse outcomes for tumour development,
(35.3% of mice, latency 48.8 weeks, p<0.02 compared
to DCA alone). Preliminary western blotting results
in MDA-MB-468 breast cancer cells found that DCA
could block the activation of AMPK by metformin, indicating
the potential for drug interactions.Supported by NHMRC Career Development Award, National Breast Cancer Foundation Novel Concept Award, and Cancer Australia
