Influences of preoperative metformin on immunological factors in early breast cancer

Tsukioki, Takahiro; Shien, Tadahiko; Tanaka, Takehiro; Suzuki, Yoko; Kajihara, Yasuhiro; Hatono, Minami; Kawada, Kenichi; Kochi, Mariko; Inomata, Takayuki; Ikeda, Hirokuni; Taira, Naruto; Doihara, Hiroyoshi; Toyooka, Shinichi

doi:10.1007/s00280-020-04092-2

Cited by 12 publications

(12 citation statements)

References 31 publications

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“…The immune-potentiating bene t of metformin is well described. Several authors have demonstrated the immunostimulatory mechanism of either metformin (9)(10)(11)(12)(13)(14) or metronomic cyclophosphamide (20) alone. To our knowledge, the combination regimen has not been investigated to date.…”

Section: Discussionmentioning

confidence: 99%

“…Several mechanistic theories explain the anti-tumor effect of metformin including direct antiproliferative effect on cancer cells, direct and systemic metabolic actions, and immune-mediated mechanisms (9,10). Following the demonstration of stimulatory effect of metformin on cytotoxic T cells in animal tumor models (11)(12)(13) and clinical studies (14), several experimental strategies were investigated with variable success, including combining metformin with radiotherapy (15), tumor vaccination (16), checkpoint blockade (17,18), and cytotoxic chemotherapy (19).…”

Section: Introductionmentioning

confidence: 99%

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Metronomic cyclophosphamide and metformin inhibited tumor growth and repopulated tumor infiltrating lymphocytes in experimental carcinoma model

Zaki,

Ali,

Allah

et al. 2023

Preprint

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Metformin is a widely used antidiabetic biguanide. Retrospective data demonstrated the association of metformin use with survival benefit in multiple tumor types. Interest in repurposing metformin to treat cancer has not been translated into encouraging clinical benefit. In animal models, metformin activated cytotoxic T cells and exerted an immune-mediated anticancer effect. The current research was conducted to investigate the possible therapeutic benefit of metformin in combination with metronomic cyclophosphamide in an experimental cancer model. Ehrlich ascites carcinoma was injected into the subcutaneous tissue to induce solid tumors in syngeneic mice. Exponential solid tumor growth ensued and was effectively arrested with the administration of a cytotoxic dose of parenteral cyclophosphamide. Alternatively, oral metformin and continuous, low-dose cyclophosphamide significantly inhibited tumor growth relative to untreated mice. The drug combination was well tolerated. Histopathological examination of the tumor showed an increased number of tumor-infiltrating lymphocytes and enhanced expression of granzyme B by this drug combination. The current data suggests a potential role of metformin and metronomic chemotherapy that warrants further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metronomic cyclophosphamide and metformin inhibited tumor growth and repopulated tumor infiltrating lymphocytes in experimental carcinoma model

Zaki,

Ali,

Allah

et al. 2023

Preprint

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“…Previous studies reported that several immune pathways were associated with the pro-tumorigenic phenotypes of immune cells and protection of tumor cells from the immune attack, ultimately favoring the development and metastasis of tumors (de Almeida et al, 2020;Tsukioki et al, 2020). The distributions of immune cells related to ADARB1 expression are shown in the bubble diagram (Figure 5A) by ssGSEA analysis of Xiantao Tool (https://www.xiantao.love/products).…”

Section: Regulation Of Immune Molecules By Adarb1mentioning

confidence: 99%

Aberrant Expression of ADARB1 Facilitates Temozolomide Chemoresistance and Immune Infiltration in Glioblastoma

et al. 2022

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Chemoresistance, especially temozolomide (TMZ) resistance, is a major clinical challenge in the treatment of glioblastoma (GBM). Exploring the mechanisms of TMZ resistance could help us identify effective therapies. Adenosine deaminases acting on RNA (ADARs) are very important in RNA modification through regulating the A-to-I RNA editing. Recent studies have shown that ADARs regulate multiple neurotransmitter receptors, which have been linked with the occurrence and progress of GBM. Here, data from several bioinformatics databases demonstrated that adenosine deaminase RNA specific B1 (ADARB1), also named ADAR2, was upregulated in both GBM tissues and cells, and had the prognostic value in GBM patients. Moreover, ADARB1 was found to be involved in AKT-mediated TMZ resistance in GBM cells. The KEGG analysis of ADARB1-associated co-expressed genes showed that ADARB1 was potentially involved in the mitochondrial respiratory chain complex. TISIDB and GEPIA databases were further used to analyze the role of ADARB1 in tumor-immune system interactions in GBM. These findings deepened our understanding of the function of ADARB1 in tumorigenesis and therapeutic response in GBM.

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“…Neoadjuvant administration of metformin has been shown to decrease IR expression and suppress PI3K and RAS/MAPK signaling in breast cancer tissues [ 24 , 99 , 100 ]. A prospective study evaluating the effects of preoperative metformin on immunological factors revealed a significant increasing trend of tumor-infiltrating lymphocytes, CD4+ and CD8+ lymphocytes, and IFN γ in response to metformin, thus suggesting an improved immune function in metformin-treated patients with early breast cancer [ 101 ].…”

Section: Metformin In Breast Cancermentioning

confidence: 99%

Metformin and Breast Cancer: Where Are We Now?

Cejuela

Martín-Castillo

Menendez

et al. 2022

IJMS

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Breast cancer is the most prevalent cancer and the leading cause of cancer-related death among women worldwide. Type 2 diabetes–associated metabolic traits such as hyperglycemia, hyperinsulinemia, inflammation, oxidative stress, and obesity are well-known risk factors for breast cancer. The insulin sensitizer metformin, one of the most prescribed oral antidiabetic drugs, has been suggested to function as an antitumoral agent, based on epidemiological and retrospective clinical data as well as preclinical studies showing an antiproliferative effect in cultured breast cancer cells and animal models. These benefits provided a strong rationale to study the effects of metformin in routine clinical care of breast cancer patients. However, the initial enthusiasm was tempered after disappointing results in randomized controlled trials, particularly in the metastatic setting. Here, we revisit the current state of the art of metformin mechanisms of action, critically review past and current metformin-based clinical trials, and briefly discuss future perspectives on how to incorporate metformin into the oncologist’s armamentarium for the prevention and treatment of breast cancer.

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Influences of preoperative metformin on immunological factors in early breast cancer

Cited by 12 publications

References 31 publications

Metronomic cyclophosphamide and metformin inhibited tumor growth and repopulated tumor infiltrating lymphocytes in experimental carcinoma model

Metronomic cyclophosphamide and metformin inhibited tumor growth and repopulated tumor infiltrating lymphocytes in experimental carcinoma model

Aberrant Expression of ADARB1 Facilitates Temozolomide Chemoresistance and Immune Infiltration in Glioblastoma

Metformin and Breast Cancer: Where Are We Now?

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