The antitumor effect of metformin with and without carboplatin on primary endometrioid endometrial carcinoma in vivo

Schrauwen, Stefanie; Coenegrachts, Lieve; Cattaneo, A.; Hermans, Els; Lambrechts, Diether; Amant, Frédéric

doi:10.1016/j.ygyno.2015.06.006

Cited by 5 publications

(3 citation statements)

References 33 publications

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“…In studies using endometrial cancer cell lines, investigators have reported a dose-dependent inhibition of cell growth with metformin treatment [ 14 – 18 ]. In mouse models, metformin treatment reduced endometrial tumor weight by nearly 50% in a xenograft model [ 17 ], but did not improve response to carboplatin in a study using two patient-derived xenograft mouse models [ 19 ]. Two retrospective analyses of patient cohorts have evaluated the association between metformin use and endometrial cancer survival.…”

Section: Introductionmentioning

confidence: 99%

Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy

et al. 2016

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There is increasing evidence that metformin, a commonly used treatment for diabetes, might have the potential to be repurposed as an economical and safe cancer therapeutic. The aim of this study was to determine whether stage III-IV or recurrent endometrial cancer patients who are using metformin during treatment with chemotherapy have improved survival. To test this we analyzed a retrospective cohort of subjects at two independent institutions who received chemotherapy for stage III-IV or recurrent endometrial cancer from 1992 to 2011. Diagnosis of diabetes, metformin use, demographics, endometrial cancer clinico-pathologic parameters, and survival duration were abstracted. The primary outcome was overall survival. The final cohort included 349 patients, 31 (8.9%) had diabetes and used metformin, 28 (8.0%) had diabetes but did not use metformin, and 291 (83.4%) did not have diabetes. The results demonstrate that the median overall survival was 45.6 months for patients with diabetes who used metformin compared to 12.5 months for patients with diabetes who did not use metformin and 28.5 months for patients without diabetes (log-rank test comparing the three groups P = 0.006). In a model adjusted for confounders, the difference in survival between the three groups remained statistically significant (P = 0.023). The improvement in survival among metformin users was not explained by better baseline health status or more aggressive use of chemotherapy. Overall, the findings in this retrospective cohort of endometrial cancer patients with stage III-IV or recurrent disease treated with chemotherapy indicate that patients with diabetes who were concurrently treated with metformin survived longer than patients with diabetes who did not use metformin.

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Section: Introductionmentioning

confidence: 99%

Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy

et al. 2016

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“…Briefly, 10 BRC016 TNBC tumorbearing NMRI-Fox1nu nude mice (Taconic) were treated intraperitoneally with 50 mg/kg carboplatin, once weekly for three weeks. The carboplatin dose chosen was based on previous studies of carboplatin-response in our lab and other groups (35,(43)(44)(45). Nine out of ten mice had a complete response to treatment.…”

Section: Pdx Modelsmentioning

confidence: 99%

Wnt/β-Catenin Inhibition Disrupts Carboplatin Resistance in Isogenic Models of Triple-Negative Breast Cancer

et al. 2021

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Triple-Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype, characterized by limited treatment options and higher relapse rates than hormone-receptor-positive breast cancers. Chemotherapy remains the mainstay treatment for TNBC, and platinum salts have been explored as a therapeutic alternative in neo-adjuvant and metastatic settings. However, primary and acquired resistance to chemotherapy in general and platinum-based regimens specifically strongly hampers TNBC management. In this study, we used carboplatin-resistant in vivo patient-derived xenograft and isogenic TNBC cell-line models and detected enhanced Wnt/β-catenin activity correlating with an induced expression of stem cell markers in both resistant models. In accordance, the activation of canonical Wnt signaling in parental TNBC cell lines increases stem cell markers’ expression, formation of tumorspheres and promotes carboplatin resistance. Finally, we prove that Wnt signaling inhibition resensitizes resistant models to carboplatin both in vitro and in vivo, suggesting the synergistic use of Wnt inhibitors and carboplatin as a therapeutic option in TNBC. Here we provide evidence for a prominent role of Wnt signaling in mediating resistance to carboplatin, and we establish that combinatorial targeting of Wnt signaling overcomes carboplatin resistance enhancing chemotherapeutic drug efficacy.

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“…Another study utilized a primary endometrioid endometrial carcinoma xenograft model using cells taken directly from patient biopsies for culture and inoculation into nude mice. The authors noted that one sample contained a K-Ras mutation while the other was wild-type; neither tumor was inhibited by metformin treatment, either alone or in combination with cisplatin (104). It should be noted that the dosage of metformin used in this study was lower than in the study by Iglesias (250 mg/kg/day for 21 days vs. 1 g/kg/day for 29-64 days).…”

Section: Cellular and Molecular Mechanisms Of Metformin Inhibition Ofmentioning

confidence: 99%

Metformin as a Therapeutic Target in Endometrial Cancers

et al. 2018

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Endometrial cancer is the most common gynecologic malignancy in developed countries. Its increasing incidence is thought to be related in part to the rise of metabolic syndrome, which has been shown to be a risk factor for the development of hyperestrogenic and hyperinsulinemic states. This has consequently lead to an increase in other hormone-responsive cancers as well e.g., breast and ovarian cancer. The correlation between obesity, hyperglycemia, and endometrial cancer has highlighted the important role of metabolism in cancer establishment and persistence. Tumor-mediated reprogramming of the microenvironment and macroenvironment can range from induction of cytokines and growth factors to stimulation of surrounding stromal cells to produce energy-rich catabolites, fueling the growth, and survival of cancer cells. Such mechanisms raise the prospect of the metabolic microenvironment itself as a viable target for treatment of malignancies. Metformin is a biguanide drug that is a first-line treatment for type 2 diabetes that has beneficial effects on various markers of the metabolic syndrome. Many studies suggest that metformin shows potential as an adjuvant treatment for uterine and other cancers. Here, we review the evidence for metformin as a treatment for cancers of the endometrium. We discuss the available clinical data and the molecular mechanisms by which it may exert its effects, with a focus on how it may alter the tumor microenvironment. The pleiotropic effects of metformin on cellular energy production and usage as well as intercellular and hormone-based interactions make it a promising candidate for reprogramming of the cancer ecosystem. This, along with other treatments aimed at targeting tumor metabolic pathways, may lead to novel treatment strategies for endometrial cancer.

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The antitumor effect of metformin with and without carboplatin on primary endometrioid endometrial carcinoma in vivo

Cited by 5 publications

References 33 publications

Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy

Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy

Wnt/β-Catenin Inhibition Disrupts Carboplatin Resistance in Isogenic Models of Triple-Negative Breast Cancer

Metformin as a Therapeutic Target in Endometrial Cancers

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