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Metformin demonstrates ability to kill cancer stem cells in mice
Clinical trials evaluating the use of metformin in cancer are underway, planned.
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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.
Cancer stem cell hypothesis
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.”
Future study, potential in humans
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.
