The
pancreatic cancer presentation last week discussed the drug Metformin, which is
one of the most widely used drugs in type 2 diabetes treatment. The presenter mentioned it interestingly has
anti-growth effects. I decided to
investigate this drug further in the context of cancer and found this study. These researchers tested the
effects of Metformin on MCF-7 human
breast cancer cells and FSaII mouse fibrosarcoma cells. The results suggest that Metformin can cause a
significant amount of clonogenic cancer cell death. Even more stunning is that the drug was
preferentially cytotoxic to cancer stem cells (CSCs) relative to non-cancer
stem cells. Also, these researchers
investigated the effect of Metformin on cancer cells being treated with
ionizing radiation and found that it increased the radiosensitivity of the
cells. In effect, the Metformin “helped”
the radiation kill the cancer cells.
This idea is very similar to my comments at the end of my presentation
last Friday in which I mentioned the possibility that drugs taken in
combination with traditional therapies could increase the desired effect
against cancer cells while decreasing the negative effects on normal
cells. This study provides some compelling
initial evidence in support of this theory.
Background Information
Metformin
is used to treat type 2 diabetes because it suppresses gluconeogenesis in the liver
and increases glucose uptake by skeletal muscle. It also decreases insulin levels in the blood
and increases insulin sensitivity.
Metformin’s anti-cancer effects were first noticed in cancer patients
who also had type 2 diabetes. Use of the
drug to treat their diabetes suppressed development of cancers in the breast,
pancreas, and lung. Also, breast cancer
patients taking this particular drug had a much better response to chemotherapy
treatment compared to cancer patients without Metformin. On the molecular level, it has been shown to
induce apoptosis and cause cell cycle arrest of cancer cells in vitro. It has also reduced incidence and growth of
tumors in vivo.
It produces
these effects by disrupting the PTEN/PI3K/Akt/mTOR signaling pathway that is
involved in cell proliferation and survival.
Metformin causes an unbalanced AMP:ATP ratio by disrupting respiration
in the mitochondria of the cell. The
increased AMP activates 5' AMP-activated protein kinase (AMPK). AMPK in turn suppresses mTOR, which is the
last link in the above signaling pathway.
Through this mechanism of action, Metformin disrupts cell proliferation. Recent studies have shown that ionizing
radiation also activates AMPK.
Therefore, Metformin can enhance the radiation-induced AMPK
activation. Through the same mechanism,
they can work together to bring down the cancer cell.
Results
The
researchers incubated MCF-7 human
breast cancer cells and FSaII mouse fibrosarcoma cells with Metformin varying
doses and times. They found that the
drug decreased the clonogenic survival of the cells at a dose and time
dependent manner (Figure 1 A-C). They also tested the
radiosensitivity of the cells by measuring clonal survival after radiation with without Metformin. The
cells incubated with the drug before and after radiation had a decreased
survival rate (Figure 1 D & E). The following figures
summarize these findings.
It was also observed that Metformin is preferentially toxic to cancer
stem cells (CSCs) relative to non-CSCs.
The researchers took advantage of multiple characteristics of CSCs to
conduct this part of the experiment, including the CD44high/CD24low
surface markers of MCF-7 cells, high level of aldehyde dehydrogenase (ALDH1) activity,
and the high activity of the ATP- binding cassette (ABC) transporter
ABCG2. The figure below illustrates the effect of Metformin on all three of these characteristics of
CSCs. Using the technique of flow
cytometry, they observed that the drug decreased the percentage of cells with
CD44high/CD24low markers, ALDH1 activity, and high activity of ABCG2.
The researchers performed another experiment that basically had the
same method and results as that of Figure 1 D & E, except they used live mice
instead of cell lines. They treated the
host mice with 25 mg Metformin/kg twice a day and irradiating the tumors one
hour after this treatment. This caused a
further decrease in tumor volume increase rate than radiation alone, as shown
in figure 7A. The x-axis of this graph
should be labeled “Number of Days”.
Figure 7. Effect of Metformin and radiation on relative tumor volume of FSaII tumors.
This drug definitely shows the potential to increase the efficacy of
radiation therapy. The article says they
observed similar effects in human MIAPaCa-2 pancreatic cancer cells and A549 cancer cells, but additional research is needed before
Metformin can be considered a realistic player in cancer therapy. Also, this drug may have adverse affects on the glucose-insulin system of cancer patients who do not have type 2 diabetes. Even so, this article does provide hope that
traditional therapies may be able to be “fixed” and not completely thrown out
in the fight against cancer.
Song, Chang
W., and Hyemi Lee. "Metformin Kills and Radiosensitizes Cancer Cells and
Preferentially Kills Cancer Stem Cells." Scientific Reports 2.362
(2012). Scientific Reports. Nature Publishing Group, 2 Apr. 2012. Web. 1
May 2012.
