Preclinical meritorious anticancer effects of Metformin against breast cancer: An In vivo trial

Rizvi, Fatima; Shaukat, Lubna; Azhar, Arfa; Jafri, Alia; Aslam, Unum; Imran-Ul-Haq, Hafiz Syed

doi:10.1016/j.jtumed.2021.02.006

Cited by 4 publications

(5 citation statements)

References 41 publications

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“…Hence, targeting OXPHOS in cancer cells may be a promising attitude toward cancer therapy. A previous study on MCF-7 cells and a total sample size of 50 athymic BALB/c mice showed that on day 7 of treatment, the tumor size of all the samples reached 100 mm 3 [ 23 ], just like what our results indicate.…”

Section: Discussionsupporting

confidence: 86%

“…The sample size was calculated by the ‘resource equation’ technique as defined by [ 22 ]. According to [ 23 ], Group A was assigned to receive metformin 150 mg/kg/day (IP injected), and Group B was assigned to receive 30 mL/kg/day PBS (IP injected) for 14 days. The number of 5 × 10 6 4T1 breast cancer cells was suspended in 100 μl of PBS mixed with 50% Matrigel (BD Biosciences) and infused into the back of the right flank of the mice.…”

Section: Methodsmentioning

confidence: 99%

“…Tumor growth ratio (V/V0): this ratio shows the tumor growth rate (TGR) per day of the experiment. V/V0 can be calculated by dividing the volume of the treatment group at a particular time by the preliminary tumor boom at baseline (earlier than starting the therapy) [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

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The anti-neoplastic effects of metformin modulate the acquired phenotype of fibroblast cells in the breast cancer-normal fibroblast co-culture system

MOSTAFAVI,

HASSAN

2024

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Intracellular communications between breast cancer and fibroblast cells were reported to be involved in cancer proliferation, growth, and therapy resistance. The hallmarks of cancer-fibroblast interactions, consisting of caveolin 1 (Cav1) and mono-carboxylate transporter 4 (MCT4) (metabolic coupling markers), along with IL-6, TGFβ, and lactate secretion, are considered robust biomarkers predicting recurrence and metastasis. In order to promote a novel phenotype in normal fibroblasts, we predicted that breast cancer cells could be able to cause loss of Cav1 and increase of MCT4, as well as elevate IL-6 and TGFβ in nearby normal fibroblasts. We created a co-culture model using breast cancer (4T1) and normal fibroblast (NIH3T3) cell lines cultured under specific experimental conditions in order to directly test our theory. Moreover, we show that long-term co-culture of breast cancer cells and normal fibroblasts promotes loss of Cav1 and gain of MCT4 in adjacent fibroblasts and increase lactate secretion. These results were validated using the monoculture of each group separately as a control. In this system, we show that metformin inhibits IL-6 and TGFβ secretion and re-expresses Cav1 in both cells. However, MCT4 and lactate stayed high after treatment with metformin. In conclusion, our work shows that co-culture with breast cancer cells may cause significant alterations in the phenotype and secretion of normal fibroblasts. Metformin, however, may change this state and affect fibroblasts’ acquired phenotypes. Moreover, mitochondrial inhibition by metformin after 8 days of treatment, significantly hinders tumor growth in mouse model of breast cancer.

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Section: Discussionsupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

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The anti-neoplastic effects of metformin modulate the acquired phenotype of fibroblast cells in the breast cancer-normal fibroblast co-culture system

MOSTAFAVI,

HASSAN

2024

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“…The biguanide metformin, an inhibitor of gluconeogenesis 12 – 14 and the most prescribed diabetes drug worldwide 15 , has been by far the most popular antihyperglycemic approach used for cancer. At supra-pharmacologic doses – several orders of magnitude higher than in human patients – metformin is capable of reducing breast cancer cell proliferation 16 – 19 , and slowing tumor growth in vivo in rodents 20 – 22 . Metformin is safe and shows good target engagement in women with breast cancer.…”

Section: Introductionmentioning

confidence: 99%

A precision medicine approach to metabolic therapy for breast cancer in mice

et al. 2022

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Increasing evidence highlights approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic drugs. To our knowledge, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach for this devastating disease. Here, we treat lean breast tumor-bearing mice with the SGLT2 inhibitor dapagliflozin as monotherapy and in combination with paclitaxel chemotherapy. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival. Further, the ability of dapagliflozin to enhance the efficacy of chemotherapy correlates with its effect to reduce circulating insulin in some but not all breast tumors. Our data suggest a genetic signature for breast tumors more likely to respond to dapagliflozin in combination with paclitaxel. In the current study, tumors driven by mutations upstream of canonical insulin signaling pathways responded to this combined treatment, whereas tumors driven by mutations downstream of canonical insulin signaling did not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach.

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“…The biguanide metformin, an inhibitor of gluconeogenesis (12)(13)(14) and the most prescribed antidiabetes drug worldwide (15), has been by far the most popular antihyperglycemic approach used for cancer. At supra-pharmacologic doses -several orders of magnitude higher than in human patients -metformin is capable of reducing breast cancer cell proliferation (16)(17)(18)(19), and slowing tumor growth in vivo in rodents (20)(21)(22). Metformin is safe and shows good target engagement in women with breast cancer.…”

Section: Introductionmentioning

confidence: 99%

A Precision Medicine Approach to Metabolic Therapy for Breast Cancer in Mice

Akingbesote

Norman

Zhu

et al. 2021

Preprint

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Increasing evidence highlights the possibility for approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic therapies, and have recently been highlighted as a novel therapeutic approach to breast cancer. To our knowledge, however, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach to combining metabolic therapy with standard of care therapy for this devastating disease. In this study we combine the SGLT2 inhibitor dapagliflozin with paclitaxel chemotherapy in both lean and obese mice. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival in an insulin-dependent manner in some but not all breast tumors. Our data find a genetic signature for breast tumors most likely to respond to dapagliflozin in combination with paclitaxel. Tumors driven by mutations upstream of canonical insulin signaling pathways are likely to respond to such treatment, whereas tumors driven by mutations downstream of canonical insulin signaling are not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that breast cancer patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach. A clinical trial is currently in preparation, with an application recently submitted for Yale Human Investigations Committee approval, to test this hypothesis in breast cancer patients.One Sentence SummaryWe identify a driver mutation signature by which glucose-wasting metabolic therapy (dapagliflozin) enhances the efficacy of chemotherapy in mice with breast cancer.

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Preclinical meritorious anticancer effects of Metformin against breast cancer: An In vivo trial

Cited by 4 publications

References 41 publications

The anti-neoplastic effects of metformin modulate the acquired phenotype of fibroblast cells in the breast cancer-normal fibroblast co-culture system

The anti-neoplastic effects of metformin modulate the acquired phenotype of fibroblast cells in the breast cancer-normal fibroblast co-culture system

A precision medicine approach to metabolic therapy for breast cancer in mice

A Precision Medicine Approach to Metabolic Therapy for Breast Cancer in Mice

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