Dr. Weeks’ Comment: Metformin is cheap and effective “centisble” medicine.
Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission
Cancer Res. Author manuscript; available in PMC 2010 October 1.
Published online 2009 September 14. doi: 10.1158/0008-5472.CAN-09-2994
Heather A. Hirsch,1,3 Dimitrios Iliopoulos,1,3 Philip N. Tsichlis,2 and Kevin Struhl1,4
1Dept. Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115
2Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111
3These authors made equal contributions to this work
4To whom correspondence should be addressed at ; Email: email@example.com
The publisher’s final edited version of this article is available free at Cancer Res
This article has been corrected. See the correction in volume 69 on page 8832.
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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 appear to remain tumor-free for at least two 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.
Chemotherapeutic treatments for cancer can effectively reduce tumor mass, but the disease often relapses. To explain this phenomenon, the cancer stem cell hypothesis suggests that tumors contain a small number of tumor-forming, self-renewing, cancer stem cells within a population of non-tumor-forming cancer cells (1, 2). Unlike most cells within the tumor, cancer stem cells are resistant to well-defined chemotherapy, and after treatment, they can regenerate all the cell types in the tumor through their stem cell-like behavior. For this reason, drugs that selectively target cancer stem cells offer great promise for cancer treatment, although none are known at present.
Epidemiological studies indicate that diabetes is correlated with increased risk of breast and other cancers (3, 4), and we recently defined a transcriptional signature and drug-sensitivity profile of cellular transformation linking multiple types of cancer with diabetes and other metabolic diseases. Metformin is an extensively used and well-tolerated drug for treating individuals with type 2 diabetes, obesity, and polycystic ovarian syndrome. Diabetics treated with metformin have reduced cancer risk (5, 6), although it is unclear whether metformin affects cancer directly or indirectly by inhibiting the diabetic state. Metformin inhibits the growth of breast cancer cell lines, although it also affects non-transformed cells at the concentrations tested (7–9). In nude mice, metformin modestly inhibits tumor growth of xenografts of a triple-negative breast cancer cell line that lacks the estrogen, progesterone, and HER2 receptors (8). These observations suggest the possibility that metformin might be useful as an anti-cancer drug in non-diabetic contexts (10, 11).
Here, we show that metformin selectively kills cancer stem cells in four genetically different types of breast cancer. The combination of metformin and doxorubicin, a well-defined chemotherapeutic drug, kills both cancer stem cells and non-stem cancer cells in culture, and reduces tumor mass and prolongs remission much more effectively than either drug alone in a xenograft mouse model. These observations constitute independent support for the cancer stem cell hypothesis, and they provide a rationale for why the combination of metformin and chemotherapeutic drugs might improve treatment of patients with breast (and possibly other) cancers. ………..
The cancer stem cell hypothesis for the progression of human disease is based on the differential tumor-forming properties and responses to well-defined chemotherapy of cancer stem cells and non-stem cancer cells. A prediction of this model, heretofore untested, is that drugs that selectively inhibit cancer stem cells should function synergistically with chemotherapeutic drugs to delay relapse. Strikingly, mice treated with the combination of metformin and doxorubicin remain in remission for at least 60 days after treatment is ended (Fig. 4A). In contrast, tumor growth resumes 20 days after mice are treated with doxorubicin alone, and the rate of tumor growth after relapse is comparable to that observed in the initial disease (i.e. in the absence of treatment). Thus, combinatorial therapy has a dramatic effect on prolonging remission, and indeed may even represent a cure of these xenograft-generated tumors. In addition to their potential medical significance, these observations provide independent and further support for the cancer stem cell hypothesis.
To our knowledge, the ability of metformin to selectively kill cancer stem cells and to function synergistically with doxorubicin to block both cancer stem cells and non-stem transformed cells is unique. In the case of breast cancer, herceptin and tamoxifen are useful drugs for cancer types that, respectively, express the HER2 and estrogen receptors, but some forms of breast cancer lack these receptors resist these treatments. For all of these types of breast cancer, metformin selectively inhibits cancer stem cell growth, and hence is likely to function synergistically with chemotherapeutic drugs. In addition, as metformin inhibits transformation of MCF10A-ER-Src cells, it might have a potential use in preventing the development of cancer, as opposed to treating cancer that has already occurred. Indeed, the ability of metformin to inhibit cellular transformation might underlie the epidemiological observation that diabetics treated with metformin have a lower incidence of cancer (5, 6). As a cancer preventative, metformin would be required on a long-term basis, and in this regard, the concentration of metformin needed for the anti-cancer effects observed here is considerably below that used for the treatment of diabetes. Lastly, the selectivity of metformin and doxorubicin for distinct types of cells in the tumor can explain the striking combinatorial effects on reducing tumor mass and prolonging remission in nude mice, and it provides the rationale for combining metformin with chemotherapy as a new treatment for breast (and possibly other) cancers.
This work was supported by a postdoctoral fellowship to H.A.H. from the American Cancer Society and research grants to P.N.T (CA 57436) and K.S. (CA 107486) from the National Institutes of Health.
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