Perturbations of cancer cell metabolism by the antidiabetic drug canagliflozin

Papadopoli, David; Uchenunu, Oro; Palia, Ranveer; Chekkal, Nabila; Hulea, Laura; Topisirović, Ivan; Pollak, Michael; St-Pierre, Julie

doi:10.1016/j.neo.2021.02.003

Cited by 27 publications

(39 citation statements)

References 41 publications

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“…An additional key point in this study is the efficacy of dapagliflozin in lean animals. Although both canagliflozin 33 , 48 , 49 , dapagliflozin 33 , empagliflozin 50 , and ipragliflozin 51 have been shown to reduce breast cancer cell division in vitro under high glucose conditions, the efficacy of any SGLT2 inhibitor has rarely been examined in vitro in glucose and insulin concentrations within the physiologic range. Even fewer studies have been performed to examine the efficacy of SGLT2 inhibitors in vivo in lean animals.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…An additional key point in this study is the efficacy of dapagliflozin in lean animals. Although both canagliflozin (33,43,44), dapagliflozin (33), empagliflozin (45), and impragliflozin (46) have been shown to reduce breast cancer cell division in vitro under high glucose conditions, the efficacy of any SGLT2 inhibitor has rarely been examined in vitro in glucose and insulin concentrations within the physiologic range. Even fewer studies have been performed to examine the efficacy of SGLT2 inhibitors in vivo in lean animals.…”

Section: Discussionmentioning

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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“…Extracellular ux. Oxygen consumption rate (OCR) and extracellular acidi cation rate (ECAR) were measured using Seahorse XFe96 instrument (Agilent Technologies, CA, USA) according to the manufacturer's protocol (52). MOLM-14 cells (750,000 cells/well) were seeded in 6-well plates.…”

Section: Methodsmentioning

confidence: 99%

“…Six wells utilized for each condition. Cells were treated for 48 hours (araC) and/or 24 hours (CR-1-31-B) and 150,000 cells/well were re-plated in 96-well Seahorse plates coated with Cell-Tak, as per the manufacturer's instructions and bioenergetic pro les were obtained as described, using the following inhibitors (1 µM oligomycin, 1.5 µM FCCP, 0.5 µM Rotenone/Antimycin A, 10 mM glucose, 50 µM 2-DG) (52). Measurements for OCR and ECAR were conducted in an XFe96 Seahorse instrument and values were normalized to cell counts.…”

Section: Methodsmentioning

confidence: 99%

EIF4A inhibition targets bioenergetic homeostasis in AML and synergizes with cytarabine and venetoclax

Fooks¹,

Galicia-Vázquez²,

Schcolnik‐Cabrera

et al. 2022

Preprint

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Background Acute myeloid leukemia (AML) is an aggressive hematological cancer resulting from uncontrolled proliferation of differentiation-blocked myeloid cells. Seventy percent of AML patients are currently not cured with available treatments, highlighting the need of novel therapeutic strategies. A promising target in AML is the mammalian target of rapamycin complex 1 (mTORC1). Clinical inhibition of mTORC1 is limited by its reactivation through compensatory and regulatory feedback loops. Here, we developed a strategy to curtail these drawbacks through inhibition of an mTORC1 target, the eukaryotic initiation factor 4A (eIF4A). Methods We tested the anti-leukemic effect of a potent and specific eIF4A inhibitor (eIF4Ai), CR-1-31-B, in combination with cytosine arabinoside (araC) or the BCL2 inhibitor venetoclax. We utilized the MOLM-14 human AML cell line to model chemoresistant disease both in vitro and in vivo. In eIF4Ai-treated cells, we assessed for changes in survival and apoptosis, de novo protein synthesis, targeted intracellular metabolite content, bioenergetic profile, mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential (MMP). Results eIF4i exhibits anti-leukemia activity in vivo while sparing non-malignant myeloid cells. In vitro, eIF4Ai synergizes with two therapeutic agents in AML, araC and venetoclax. eIF4Ai reduces mitochondrial membrane potential (MMP), the rate of ATP synthesis from mitochondrial respiration and glycolysis, and the expression of the antiapoptotic factors BCL2 and MCL1. Concomitantly, eIF4Ai decreases intracellular levels of specific metabolic intermediates of the tricarboxylic acid cycle (TCA cycle) and glucose metabolism, while enhancing mtROS. In vitro redox stress contributes to eIF4Ai cytotoxicity. Conclusions We discovered that AML cells rely on eIF4A-dependent cap translation for survival in vitro and in vivo. Our work indicates that eIF4A drives an intrinsic metabolic program sustaining bioenergetic and redox homeostasis. Furthermore, our work suggests that eIF4A-dependent cap translation contributes to adaptive processes involved in resistance to relevant therapeutic agents in AML.

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Perturbations of cancer cell metabolism by the antidiabetic drug canagliflozin

Cited by 27 publications

References 41 publications

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

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

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

EIF4A inhibition targets bioenergetic homeostasis in AML and synergizes with cytarabine and venetoclax

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