Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission

By Heather A. Hirsch, D. Iliopoulos, P. Tsichlis, Kevin Struhl. Cancer Research, 2009

1,125 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Molecular Biology, Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/d15b50b33ca0b195acca2fa9bb70437048cfb287

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Citations in the corpus

Targeting cancer metabolism: a therapeutic window opens (2011, background): “However, high doses of metformin are toxic to cancer stem cell”
An epigenetic switch involving NF-κB, Lin28, let-7 microRNA, and IL6 links inflammation to cell transformation (2009, positive): “Transient Activation of Src Causes an Epigenetic Switch from Normal to Transformed Cells We described an experimental model of oncogenesis involving a derivative of MCF10A, a spontaneously immortalized cell line derived from normal mammary epithelial cells (Soule et al., 1990), that contains ER-Src,”
The genetic basis of kidney cancer: a metabolic disease (2010, background): “Metformin use has been associated with a decreased cancer mortality in type II diabetics(85;86) and has been shown to block tumor growth in combination with chemotherapeutic agents in preclinical in vitro and in vivo models of cancer.(87;88) Although metformin is taken by patients with type II diabe”
Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality. (2015, background): “Finally, metformin may selectively kill breast cancer stem cells and prevent tumor recurrence in mouse xenografts (77).”
Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion (2011, methodology): “For ER-Src– transformed cells, MCF7 and MDA-MB-231 cancer cells, to separate CSCss from NSCCs, flow cytometric cell sorting was performed on single-cell suspensions that were stained with CD44 antibody (FITC-conjugated) (555478; BD Biosciences) and with CD24 antibody (PE-conjugated) (555428; BD Bios”
Molecular mechanisms of cancer development in obesity (2011, background): “A growing body of data demonstrates that metformin and TZDs may have anti-tumorigenic effects in many model systems, either as single agents or in combination with conventional chemotherap”
Targeting Epithelial–Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer (2016, background): “, reported that metformin selectively targets breast cancer stem cells (BCSCs) [77].”
Cellular and molecular mechanisms of metformin: an overview. (2012, methodology): “Breast 2 mg/ml Oral [138] Leukemia 250 mg/kg IP [124] Cancer stem cells 100 μg/ml IP [159] chemically-induced Breast 50-500 mg/kg Oral [160] Lung 250 mg/kg IP [161] Colon 250 mg/kg IP [162] Pancreas 320 mg/kg Oral [115] HER2/neu mice Breast 100 mg/kg Oral [118] PTEN mice All 300 mg/kg Oral [119] APC”
Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. (2012, background): “In vitro and in vivo cancer studies show the antiproliferative capacity of this drug, and its ability to induce death in a stem cell model of breast carcinoma.(76) Furthermore, a retrospective study linked metformin use with a higher probability of pCR in the neoadjuvant setting.”
EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer (2010, background): “Finally, activation of the AMP-activated kinase with the diabetes drug metformin results in selective killing of CSCs in combination with chemotherapy (Hirsch et al., 2009).”