Introduction:
Metformin is used as a first-line treatment in type 2 diabetes. Several
studies suggest that patients with type 2 diabetes treated with
metformin may have a reduced cancer risk. Recently it has been shown
that metformin acts directly on mitochondria to alter cellular
bioenergetics and reduce tumorigenesis. We have shown that
anti-proliferative effect of mitotane is related to changes in
expression of the genes involved in mitochondrial metabolism in human
adrenocortical (H295R), breast, lung and colon cancer (ENDO 2015). Aim:
As both metformin and mitotane affect mitochondrial metabolism, the
objective of the study was to assess the impact of combined treatment
with metformin and mitotane on H295R cell line proliferation. Material
and Methods: Human adrenocortical cancer cell lines (H295R) were
cultured in 96 well plates, and cell proliferation rate was assessed by
resazurin assay. Results: The maximum effect of metformin was observed
at 48-hours of incubation, resulting in cytotoxicity of 6, 16, 28 and
55% at the concentration of 5, 10, 20 and 40mM, respectively. The
maximum effect of mitotane (10uM) was observed at 24-hours of
incubation, resulting in 30% of cytotoxicity and this concentration was
used in combined treatments with metformin. Even though both compounds
inhibited proliferation separately, combined treatment led to either
total loss of their anti-proliferative effect (metformin at the
concentration of 5 and 10mM) or a significant decrease in cytotoxicity
to 9 (p<0.001) and 44% (p<0.001) for metformin at the
concentration of 20 and 40mM, respectively. Conclusions: Those
preliminary results shows that even though metformin alone can have an
anti-proliferative effect on H295R cell line, it should be added to
mitotane with caution as it can negatively alter the cytotoxic effect of
mitotane. The studies require further exploration to understand this
unexpected mechanism. - See more at
http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2016.AHPAA.3.SAT-411#sthash.qoPhRUpy.dpu