title: Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission.
abstract: 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.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02115, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Hirsch
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
authors.forename: Kevin
authors.initials: K
authors.lastname: Struhl
mesh_terms: D000328:Adult; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D004317:Doxorubicin; D008687:Metformin