Anticancer Effects of Metformin and Its Potential Use as a Therapeutic Agent for Breast Cancer

Guppy, Amy; Jamal‐Hanjani, Mariam; Pickering, Lisa

doi:10.2217/fon.11.49

Cited by 41 publications

(29 citation statements)

References 67 publications

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“…The lower risk of colon cancer associated with metformin use (Tables 2 and 3) was in agreement with the earlier meta-analyses (19,21) and supported the preliminary clinical trial by Hosono et al (22). Together, these studies provided a strong rationale for undertaking larger clinical trials to investigate the cancer-protecting effects of metformin on various human malignancies including colon cancer (23,24).…”

Section: Discussionsupporting

confidence: 85%

“…This study strongly indicated a potential inhibitory effect of metformin on colorectal carcinogenesis. Currently, more than ten ongoing clinical trials are aimed at investigating the anticancer effects of metformin on various human malignancies involving the breast, prostate, pancreas, endometrium, kidney, lung, lymphoma, and others (23,24).…”

Section: Introductionmentioning

confidence: 99%

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Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan

Tseng

2012

European Journal of Endocrinology

120

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Objective: A retrospective cohort study, using a population-based reimbursement database, was conducted for investigating the relationship between diabetes and colon cancer and assessing whether metformin had a protective effect. Methods: Overall, 493 704 men and 502 139 women, covered by the National Health Insurance, without colon cancer were followed from 2003 to 2005. Cox regression evaluated the adjusted relative risk (RR), considering confounders and detection examinations. Results: Even though diabetes patients had a significantly higher probability of receiving examinations that could lead to the detection of colon cancer, they had a significantly higher risk (24%) of this cancer after adjustment. Metformin users had a significantly lower risk (27%) of colon cancer. While comparing patients with diabetes for !1, 1-3, and R3 years to nondiabetes individuals, the adjusted RR (95% confidence interval) was 1.308 (1.020-1.679), 1.087 (0.900-1.313), and 1.185 (1.055-1.330) respectively. The higher risk among those with diabetes for !1 year suggested a possible reverse causality or a link with prediabetes. However, diabetes still might play some role in the development of colon cancer in those with diabetes for R3 years. The duration of metformin use showed an inverse trend, with a significant RR of 0.643 (0.490-0.845) in users for R3 years, when compared with nonusers. In addition, metformin may reduce colon cancer risk associated with chronic obstructive pulmonary disease (a surrogate for smoking). Conclusions: Following adjustment for potential detection bias and other covariates, diabetes remains a significant risk factor for colon cancer. Metformin may protect against colon cancer.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan

Tseng

2012

European Journal of Endocrinology

120

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“…18 In light of these findings, metformin is now being tested in several clinical trials in patients with solid tumors, especially breast cancer. 19 A recent paper has highlighted the cytotoxicity of metformin in preclinical models of acute myelogenous leukemia (AML), 20 emphasizing the effects of metformin on the translation of oncogenic proteins. We have recently demonstrated that inhibition of mTORC1-mediated oncogenic protein translation occurs also in T-ALL cells treated with mTORC1/mTORC2 ATP-competitive inhibitors, but not with rapamycin.…”

Section: Introductionmentioning

confidence: 99%

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

et al. 2011

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The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic subunit of two multi-protein complexes, referred to as mTORC1 and mTORC2. Signaling downstream of mTORC1 has a critical role in leukemic cell biology by controlling mRNA translation of genes involved in both cell survival and proliferation. mTORC1 activity can be down-modulated by upregulating the liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway. Here, we have explored the therapeutic potential of the anti-diabetic drug, metformin (an LKB1/AMPK activator), against both T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples from T-ALL patients displaying mTORC1 activation. Metformin affected T-ALL cell viability by inducing autophagy and apoptosis. However, it was much less toxic against proliferating CD4(+) T-lymphocytes from healthy donors. Western blot analysis demonstrated dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found a marked inhibition of mRNA translation in T-ALL cells treated with metformin. Remarkably, metformin targeted the side population of T-ALL cell lines as well as a putative leukemia-initiating cell subpopulation (CD34(+)/CD7(-)/CD4(+)) in patient samples. In conclusion, metformin displayed a remarkable anti-leukemic activity, which emphasizes future development of LKB1/AMPK activators as clinical candidates for therapy in T-ALL. Leukemia (2012) 26, 91-100; doi:10.1038/leu.2011.269; published online 4 October 201

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“…Recent interest has focused on cell signaling pathways controlling both cell metabolism and cell growth. 4,5 And also, the association of reduced cancer risk and edible food has also captured the interests of scientists.…”

Section: Introductionmentioning

confidence: 99%

Diarylbutane-type Lignans fromMyristica fragrans(Nutmeg) show the Cytotoxicity against Breast Cancer Cells through Activation of AMP-activated Protein Kinase

Nguyen

Choi

et al. 2017

Nat Prod Sci

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-In our program to search for new AMP-activated protein kinase (AMPK) activators from plants that exert potential anticancer property, we found that an EtOAc extract of Myristica fragrans (nutmeg) activated AMPK enzyme in human breast cancer MCF-7 cells. Two major diarylbutane-type lignans, macelignan and meso-dihydroguaiaretic acid (MDGA), were isolated as active principles from this extract. Treatment of breast cancer cells with two compounds induced cellular apoptosis, evidenced by cleavage of poly-(ADP-ribose) polymerase (PARP) and Ser 15 phosphorylation of p53. Moreover, macelignan and MDGA significantly inhibited the colony formation of MCF-7 breast cancer cells on soft agar. Intraperitoneal injection of macelignan and MDGA (20 mg/kg) suppressed the tumor growth of 4T1 mammary cancer cells. These results indicate that the chemopreventive effects of two major diarylbutane-type lignans from Myristica fragrans (nutmeg) may be associated with induction of apoptosis presumably through AMPK activation.

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Anticancer Effects of Metformin and Its Potential Use as a Therapeutic Agent for Breast Cancer

Cited by 41 publications

References 67 publications

Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan

Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

Diarylbutane-type Lignans fromMyristica fragrans(Nutmeg) show the Cytotoxicity against Breast Cancer Cells through Activation of AMP-activated Protein Kinase

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