Phase 2 Trial of Metformin Combined With 5-Fluorouracil in Patients With Refractory Metastatic Colorectal Cancer

Miranda, Vanessa da Costa; Braghiroli, Maria Ignez; Faria, Luiza Dib Batista Bugiato; Bariani, Giovanni M.; Alex, Alexandra; Neto, João Batista de Andrade; Capareli, Fernanda; Sabbaga, Jorge; Santos, Juliana Ferreira Lobo dos; Hoff, Paulo M.; Riechelmann, Rachel P.

doi:10.1016/j.clcc.2016.04.011

Cited by 70 publications

(47 citation statements)

References 25 publications

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“…Therefore, compounds sensitizing CRC cells to these routinely used drugs are urgently required to improve therapeutic outcome. Metformin is a promising candidate, as documented by several clinical trials (61,62). The results of the present study demonstrated that metformin augmented the anticancer activity of 5-FU and oxaliplatin, and that the effect was enhanced in CRC cells with disrupted AGR2 expression.…”

Section: Discussionmentioning

confidence: 99%

AGR2 silencing contributes to metformin‑dependent sensitization of colorectal cancer cells to chemotherapy

et al. 2019

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There is growing epidemiological evidence indicating an association between diabetes mellitus and the increased incidence of colorectal cancer (CRC). The preferred initial and most widely used pharmacological agent for the treatment of type 2 diabetes is metformin, which in parallel reduces the risk of CRC and improves patient prognosis. AMP-activated protein kinase (AMPK) appears to be tightly associated with the beneficial metabolic effects of metformin, serving as a cellular energy sensor activated in response to a variety of conditions that deplete cellular energy levels. Such conditions include nutrient starvation (particularly glucose), hypoxia and exposure to toxins that inhibit the mitochondrial respiratory chain complex. The aim of the present study was to determine the effect of metformin on CRC cell lines, with different levels of anterior gradient 2 (AGR2) expression, exposed to 5-fluorouracil (5-FU) and oxaliplatin, alone or in combination with metformin. AGR2 has recently emerged as a factor involved in colon carcinogenesis. In AGR2-knockout cells, markedly higher levels of phosphorylated-AMPK were observed in comparison with control cells transfected with GFP-scrambled guide RNA, which indicated that the presence of AGR2 may interfere with the metformin-dependent activation of AMPK. In addition, metformin in combination with 5-FU and oxaliplatin induced ROS production and attenuated autophagy. This effect was enhanced in AGR2-knockout cells.

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Section: Discussionmentioning

confidence: 99%

AGR2 silencing contributes to metformin‑dependent sensitization of colorectal cancer cells to chemotherapy

et al. 2019

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“…The indirect tumor-inhibiting pathway of metformin may be more effective for obesity-related cancer such as colon, 24 breast, 25 and endometrium cancers (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

Association of Metformin Use and Survival Outcome in Women With Cervical Cancer

Takiuchi

Machida

Hom

et al. 2017

Int J Gynecol Cancer

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“…This contraindication suggests that p53 may not be a reliable companion biomarker to predict response to metformin. Lymph node invasion FIT-CRC-086 Adenocarcinoma Rectum 1 Ulcerated 4 IVA 3 0 1a 0/7 FIT-CRC-104 Mucinous adenocarcinoma Ascending colon 2 Localized 5 IIA 3 0 0 0/39 Studies from a recent phase II clinical trial evaluating metformin and 5-FU in patients with refractory colorectal cancer showed only a mild median progression-free survival (PFS) of 1.8 months and median overall survival (OS) of 7.9 months, with a majority of patients (78%) having disease progression before 8 weeks (42). For 11 out of 50 patients (22%) having stable disease at the end of 8 weeks, their median PFS and OS were 5.6 months and 16.2 months, respectively.…”

Section: Discussionmentioning

confidence: 99%

Metformin Inhibits Cellular Proliferation and Bioenergetics in Colorectal Cancer Patient–Derived Xenografts

Suhaimi

Phyo

Yap

et al. 2017

Molecular Cancer Therapeutics

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There is increasing preclinical evidence suggesting that metformin, an antidiabetic drug, has anticancer properties against various malignancies, including colorectal cancer. However, the majority of evidence, which was derived from cancer cell lines and xenografts, was likely to overestimate the benefit of metformin because these models are inadequate and require supraphysiologic levels of metformin. Here, we generated patient-derived xenograft (PDX) lines from 2 colorectal cancer patients to assess the properties of metformin and 5-fluorouracil (5-FU), the first-line drug treatment for colorectal cancer. Metformin (150 mg/kg) as a single agent inhibits the growth of both PDX tumors by at least 50% ( < 0.05) when administered orally for 24 days. In one of the PDX models, metformin given concurrently with 5-FU (25 mg/kg) leads to an 85% ( = 0.054) growth inhibition. culture of organoids generated from PDX demonstrates that metformin inhibits growth by executing metabolic changes to decrease oxygen consumption and activating AMPK-mediated pathways. In addition, we also performed genetic characterizations of serial PDX samples with corresponding parental tissues from patients using next-generation sequencing (NGS). Our pilot NGS study demonstrates that PDX represents a useful platform for analysis in cancer research because it demonstrates high fidelity with parental tumor. Furthermore, NGS analysis of PDX may be useful to determine genetic identifiers of drug response. This is the first preclinical study using PDX and PDX-derived organoids to investigate the efficacy of metformin in colorectal cancer..

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Phase 2 Trial of Metformin Combined With 5-Fluorouracil in Patients With Refractory Metastatic Colorectal Cancer

Cited by 70 publications

References 25 publications

AGR2 silencing contributes to metformin‑dependent sensitization of colorectal cancer cells to chemotherapy

AGR2 silencing contributes to metformin‑dependent sensitization of colorectal cancer cells to chemotherapy

Association of Metformin Use and Survival Outcome in Women With Cervical Cancer

Metformin Inhibits Cellular Proliferation and Bioenergetics in Colorectal Cancer Patient–Derived Xenografts

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