Combo with anti-diabetes drug found effective against cancer
(AFP) – 1 day ago
SAN FRANCISCO —
An anti-diabetes drug reduced tumors faster and prolonged remission further than chemotherapy when tested on mice, apparently by targeting cancer stem cells, a new report by Harvard Medical School found.
The report, published Monday in the online journal Cancer Research, argued that the drug metformin may improve breast cancer outcomes in people.
"We have found a compound selective for cancer stem cells," said senior author Kevin Struhl, a professor of biological chemistry and molecular pharmacology at Harvard Medical School. "What's different is that ours is a first-line diabetes drug."
In this study, the diabetes drug seemed to work independently of its ability to improve insulin sensitivity and lower blood sugar and insulin levels, all of which are also associated with better breast cancer outcomes.
The combination of metformin and the cancer drug doxorubicin killed human cancer stem cells and non-stem cancer cells in culture, the report said. The researchers used four genetically distinct breast cancer cell lines.
In mice, pretreatment with the diabetes drug prevented the otherwise dramatic ability of human breast cancer stem cells to form tumors.
In other mice where tumors were allowed to take hold for 10 days, the dual therapy also reduced tumor mass more quickly and prevented relapse for longer than doxorubicin alone, accordign to the study.
In the two months between the end of treatment and the end of the experiment, tumors regrew in mice treated with chemotherapy alone, but not in mice that had received both drugs.
By itself, metformin was ineffective in treating tumors.
"There is a big desire to find drugs specific to cancer stem cells," Struhl explained.
"The cancer stem cell hypothesis says you cannot cure cancer unless you also get rid of the cancer stem cells. From a purely practical point of view, this could be tested in humans. It's already used as a first-line diabetes drug."
Diabetes drug kept breast tumors away in mice
Mon Sep 14, 2009 7:45pm BST
By
Julie Steenhuysen
CHICAGO (Reuters) -
Adding the common diabetes drug metformin to chemotherapy helped shrink breast cancer tumors faster in mice and keep them away longer than chemotherapy alone, raising hope for a more effective way to treat cancer, U.S. researchers said on Monday.
They said metformin appeared to target breast cancer stem cells -- a kind of master cancer cell that resists conventional treatment and may be the source of many tumors that grow back.
"What's exciting here is
we now have something that is mechanistically a different kind of killer of cancer that can synergize with chemotherapy," Kevin Struhl of Harvard Medical School, whose study appears in the journal Cancer Research, said in a telephone briefing.
Many teams have been looking for ways to destroy the master cancer cells in the hope of making cancer easier to cure.
Last month, a team at the Broad Institute of Harvard and the Massachusetts Institute of Technology reported that a chemical called salinomycin could kill breast cancer stem cells.
What is different with his study, Struhl said, is that metformin is a widely used drug with a long safety track record. "There are tens of millions of people who take this drug," he said.
"Although our studies are limited to mice and cells, metformin has a history of anti-cancer effects," he said.
Metformin has already been shown to reduce the risk of some cancers, including pancreatic and breast cancer, in large studies of people with diabetes.
Struhl said
metformin's affect on cancer stem cells appeared to be separate from its ability to help the body use insulin and lower blood sugar -- which also can improve breast cancer survival.
His team studied metformin and the cancer drug doxorubicin in lab dishes and found they
killed both human cancer stem cells and non-stem cancer cells.
Mice that had tumors and got metformin and chemotherapy were less likely to have tumors grow back two months after treatment compared with mice that got chemotherapy alone.
"When we had both drugs together, we lost the tumors faster, but more importantly, there was no relapse," Struhl said.
He said with metformin, it may be possible to reduce the chemotherapy dose and still get the same benefit.
That will need to be studied in people and a study is getting under way. Dr. Jennifer Ligibel, at Dana-Farber Cancer Institute and Harvard, is organizing a large trial with colleagues in Canada to study metformin in women with early stage breast cancer.
- 1: Cancer Res. 2009 Sep 14. [Epub ahead of print]
Links
- Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission.
Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
The cancer stem cell hypothesis suggests that, unlike most cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease. Thus, drugs that selectively target cancer stem cells offer great promise for cancer treatment, particularly in combination with chemotherapy. Here, we show that low doses of metformin, a standard drug for diabetes, inhibits cellular transformation and selectively kills cancer stem cells in four genetically different types of breast cancer. The combination of metformin and a well-defined chemotherapeutic agent, doxorubicin, kills both cancer stem cells and non-stem cancer cells in culture. Furthermore, this combinatorial therapy reduces tumor mass and prevents relapse much more effectively than either drug alone in a xenograft mouse model. Mice seem to remain tumor-free for at least 2 months after combinatorial therapy with metformin and doxorubicin is ended. These results provide further evidence supporting the cancer stem cell hypothesis, and they provide a rationale and experimental basis for using the combination of metformin and chemotherapeutic drugs to improve treatment of patients with breast (and possibly other) cancers. [Cancer Res 2009;69(19):OF1-5].