Low doses of the antidiabetic treatment metformin, combined with the
chemotherapeutic agent doxorubicin, demonstrated reduction in tumor size and
prolonged remission in mice injected with human breast cancer cells, according
to data published online today.
Kevin Struhl, PhD, a David Wesley Gaiser professor of biological
chemistry and molecular pharmacology at Harvard Medical School, and colleagues
treated mice with tumors generated with MCF-10A human breast cancer cells; the
mice received either doxorubicin, metformin or the combination of the two
drugs. Researchers used a metformin dose of 0.1 mmol/L or 0.3 mmol/L, which is
a considerably lower concentration than that used for diabetes treatment and
one that does not affect the growth of nontransformed cells.
“Metformin is a selective killer of cancer stem cells, and, as a
consequence, it works in combination with standard chemotherapy to both
increase the rate at which the tumor regresses and more importantly to delay
relapse,” Struhl said during a press conference this morning.
“Metformin is well known and is a safe drug with a human history of having
some effect in cancer. In addition, it works at quite low doses — lower
than typically used in many diabetes studies. For all these reasons, we think
there is a lot of promise for potential as a cancer treatment.”
The researchers also cultured cell lines for three other human breast
cancers that represented ER, HER and triple-negative breast cancers. They found
that pretreatment with metformin prevented the human breast cancer stem cells
from forming tumors. Metformin and doxorubicin worked together to reduce both
cancer stem cells and non-stem cancer cells. The researchers wrote that after
15 days of treatment (three cycles every five days), the combination
“virtually eliminated” tumors, while doxorubicin alone caused a
twofold decrease in tumor volume and metformin alone had little effect.
At the time of the conference call, Struhl said the mice that received
the combined treatment were close to achieving three months in remission.
However, in those mice treated with doxorubicin alone, tumor growth resumed 20
days after treatment, and the rate of the tumor growth was comparable with that
observed before treatment.
“None of these breast cancer lines have anything to do with
diabetes, so this drug is working in a cancer context quite independently of a
classic diabetes situation,” Struhl said.
The results of the combined therapy provide further evidence to support
the cancer stem cell hypothesis, according to the researchers. This hypothesis
says that, unlike most cancer cells in a tumor, cancer stem cells resist
chemotherapeutic drugs and can regenerate the various cell types in the tumor,
therefore causing relapse. Drugs that selectively target cancer stem cells
— like metformin appears to do in this study — offer promise for
cancer treatment, particularly in combination with chemotherapy.
“We now have something that is a mechanistically different kind of
killer in cancer, namely a cancer stem cell killer that can synergize with
classic chemotherapy,” Struhl said. “Although our studies are limited
to mice and cells, metformin has a history of anticancer effects. In
particular, patients with diabetes who are treated with metformin have a much
lower incidence of cancer than people with diabetes not treated with
metformin.”
Research on metformin’s use in cancer is ongoing. Jennifer
Ligibel, MD, of the Dana-Farber Cancer Institute and Harvard Medical
School, is collaborating with Pamela Goodwin, MD, and her colleagues at the
National Cancer Institute of Canada Clinical Trials group to develop a phase-3
study that will evaluate metformin’s influence on recurrence in women
treated for early-stage breast cancer. Ligibel said she and her colleagues hope
to begin enrollment into the study, called MA32, by next year. In the study,
women who have finished treatment will be randomly assigned to three years of
metformin vs. placebo. “This will really start to look at whether taking
metformin after standard chemotherapy does reduce the risk of cancer
recurrence,” Ligibel said during the press conference.
According to Ligibel, other studies, some completed and some ongoing,
involve looking at metformin alone before surgery to analyze what happens in
cancer as metformin is administered. “This will really allow us to look at
some of these hypotheses in patients, as well as this very interesting early
mouse and cancer cell line data,” Ligibel said. “Dr. Struhl’s
paper will also increase interest in combining metformin with chemotherapy,
which hasn’t been done clinically at this point.”
Struhl said that unlike new agents in cancer, trials with metformin can
begin immediately. “What we really await are tests in humans where one is
really trying to see how to use metformin in the optimal way, how to use it
together with chemotherapy, whether the dose of chemotherapy be reduced and
what other cancers can it work for,” he said. “Because metformin is a
well-used drug and basically safe, the clinical trials really can start almost
immediately.” – by Tina DiMarcantonio
Hirsch HA et al. Cancer Res.
2009;doi:10.1158/0008-5472.CAN-09-2994.
