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Serine Deprivation Enhances Antineoplastic Activity of Biguanides
Abstract
Metformin, a biguanide widely used in the treatment of type II diabetes, clearly exhibits antineoplastic activity in experimental models and has been reported to reduce cancer incidence in diabetics. There are ongoing clinical trials to evaluate its antitumor properties, which may relate to its fundamental activity as an inhibitor of oxidative phosphorylation. Here, we show that serine withdrawal increases the antineoplastic effects of phenformin (a potent biguanide structurally related to metformin). Serine synthesis was not inhibited by biguanides. Instead, metabolic studies indicated a requirement for serine to allow cells to compensate for biguanide-induced decrease in oxidative phosphorylation by upregulating glycolysis. Furthermore, serine deprivation modified the impact of metformin on the relative abundance of metabolites within the citric acid cycle. In mice, a serine-deficient diet reduced serine levels in tumors and significantly enhanced the tumor growth–inhibitory actions of biguanide treatment. Our results define a dietary manipulation that can enhance the efficacy of biguanides as antineoplastic agents that target cancer cell energy metabolism. Cancer Res; 74(24); 7521–33. ©2014 AACR.
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“Additionally, serine deprivation by dietary restriction is sufficient to slow growth of both xenograft (Gravel et al., 2014; Maddocks et al., 2013) and autochthonous cancer models, although efficacy of serine deprivation appears to be influenced by both the oncogenic driver mutation and tissue context (Maddocks et al., 2017).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Gravel et al., 2014
In the citing paper
“Combining serine restriction with other drugs may also potentiate antitumor responses (Gravel et al., 2014; Maddocks et al., 2013; Maddocks et al., 2017).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Gravel et al., 2014
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Metadata
- Authors
- Gravel, S.-P., Hulea, L., Toban, N., Birman, E., Blouin, M.-J., Zakikhani, M., Zhao, Y., Topisirovic, I., St-Pierre, J., & Pollak, M.
- Affiliations
- McGill University (CA)
- Jewish General Hospital (CA)
- 2Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
- 1Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
- 3Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
- Venue
- Cancer Research
- Published
- 2014-12-14
- Volume
- 74
- Issue
- 24
- Pages
- 7521-7533
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2016133306
- Cited by
- 138
- References
- 47
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 13 · 2023: 14 · 2022: 15 · 2021: 24 · 2020: 15 · 2019: 13 · 2018: 8 · 2017: 7 · 2016: 11 · 2015: 5
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP115-195, FRN53888, 106603_1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- biguanides, metformin, phenformin, anticancer activity, oxidative phosphorylation inhibition, glycolysis, cancer cell energy metabolism, tumor growth inhibition, dietary intervention
- MeSH terms
- Animals, Biguanides, Glycolysis, Humans, Metformin, Neoplasms, Oxidative Phosphorylation, Phenformin, Serine, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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