Effect of dapagliflozin on colon cancer cell [Rapid Communication]

Saito, Tsugumichi; Okada, Shuichi; Yamada, Eijiro; Shimoda, Yoko; Osaki, Aya; Tagaya, Yuko; Shibusawa, Ryo; Okada, Junichi; Yamada, Masanobu

doi:10.1507/endocrj.ej15-0396

Cited by 49 publications

(46 citation statements)

References 9 publications

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“…Therefore, these findings suggest that canagliflozin may protect against gastrointestinal cancer by suppressing the expression of both SGLT1 and SGLT2 in the gastrointestinal tract. In a study of human colon cancer cells not expressing UGT1A9, which encodes the enzyme for metabolising SGLT2 inhibitors, dapagliflozin significantly reduced the number of colon cells [79]. However, our meta-analysis did not detect a decreased risk of gastrointestinal cancer with the use of dapagliflozin or empagliflozin.…”

Section: Discussioncontrasting

confidence: 73%

SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials

et al. 2017

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Section: Discussioncontrasting

confidence: 73%

SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials

et al. 2017

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“…The principal metabolic pathway and the main energy source of tumor cells are glycolysis and glucose, respectively, and SGLT2 plays an important role in glycolysis and glucose in tumor cells [13–15]. However, there is little known about the relationship between SGLT2 and renal cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Effect of Sodium Glucose Co-Transporter 2 Inhibitor Dapagliflozin on Renal Cell Carcinoma

et al. 2017

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BackgroundPatients with type 2 diabetes mellitus (T2DM) have a high incidence of renal cell carcinoma (RCC) and high sodium glucose co-transporters 2 (SGLT2) expressions. The purpose of this study was to evaluate the anticancer activity of dapagliflozin as an SGLT2 inhibitor on RCC cell lines in vitro and in vivo.Material/MethodsqRT-PCR and Western blot were used to detect SGLT2 expression on different human renal cells. Then, flow cytometry and immunofluorescence were used to investigate the effects of dapagliflozin on cell cycle, apoptosis, and SGLT2 expression of CaKi-1 cells. Finally, a xenograft model and immunohistochemical staining were used to investigate the function of dapagliflozin in nude mice.ResultsWe proved that SGLT2 is highly expressed in RCC cell lines. We found that dapagliflozin exerts a higher cytotoxic effect on human RCC than on normal human renal cells, regulates the cell cycle and apoptosis, and reduces the glucose uptake and SGLT2 expression of CaKi-1 cells. Moreover, dapagliflozin inhibits tumor growth and reduces SGLT2 expression in vivo.ConclusionsOur results indicate that dapagliflozin has high efficiency and low toxicity and could be a new therapeutic target for RCC.

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“…As mentioned above, the SGLT family proteins are involved in the active uptake of glucose, with predominant expression in intestine and kidney (Vrhovac et al, 2015). Moreover, it has been reported that functional SGLT2 expression is detected in various cancer types, including lung, pancreatic, prostate, colon, and liver cancers (Ishikawa et al, 2001;Kaji et al, 2018;Saito et al, 2015;Scafoglio et al, 2015;Scafoglio et al, 2018;Villani et al, 2016). Indeed, all 6 NSCLC cell lines expressed SGLT2 (Figure 6A).…”

Section: Cellsmentioning

confidence: 74%

“…Indeed, all 6 NSCLC cell lines expressed SGLT2 (Figure 6A). Targeting SGLT2 by its inhibitors has been shown to inhibit tumor cell growth in pancreatic, prostate, colon, liver and lung cancers (Kaji et al, 2018;Saito et al, 2015;Scafoglio et al, 2015;Scafoglio et al, 2018;Villani et al, 2016). Thus, it is of interest and importance to investigating whether SGLT2 inhibitors would mimic the effect of glucose starvation in selective killing of the EGFR-WT/LKB1-mutant NSCLC cells.…”

Section: Cellsmentioning

confidence: 99%

Synthetic lethality targeting LKB1 mutant and EGFR wild type human non-small cell lung cancer cells by glucose starvation and SGLT2 inhibition

Ren

Chen

et al. 2019

Preprint

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In this study, we aimed to discover novel therapeutic approaches targeting non-small cell lung cancer (NSCLC) patients without EGFR mutation. First, we found that mutations of EGFR and LKB1 are mutually exclusive in NSCLC. EGFR-WT/LKB1-mutant cells are resistant to EGFR inhibitor erlotinib but are highly susceptible to glucose starvation or SGLT2 inhibitor canagliflozin. Mechanistically, in these cells, glucose starvation causes suppression of AMPK and induction of oxidative stress, leading to cell death. Finally, canagliflozin effectively reduces tumor growth of EGFR-WT/LKB1-mutant NSCLC cells in the mice xenograft model. Our data thus demonstrate that synthetic lethality can be achieved by glucose starvation or SGLT2 inhibition in EGFR-WT/LKB1-mutant NSCLC. SIGNIFICANCEAt present, EGFR inhibitor-based targeted therapy can only benefit those non-small cell lung cancer (NSCLC) patients with EGFR mutation. Therefore, there is an urgent need to develop alternate targeted therapy for NSCLC with WT EGFR. In this study, we found that mutations of EGFR and LKB1 are mutually exclusive in NSCLC, and more importantly, synthetic lethality can be achieved in EGFR-WT/LKB1-mutant NSCLC cells with glucose starvation or SGLT2 inhibition. Since SGLT2 inhibitors such as canagliflozin are FDA-approved drugs for type II diabetes, our study thus points out a possibility of developing SGLT2 inhibitors as a targeted therapy for NSCLC patients with WT EGFR and mutant LKB1, which will benefit about 15-30% of NSCLC patients. HIGHLIGHTS• EGFR and LKB1 mutations are mutually exclusive in NSCLC• EGFR-WT/LKB1-mutant NSCLC cells are sensitive to cell death induced by glucose starvation and SGLT2 inhibition • Glucose starvation suppresses AMPK activity in LKB1-mutant NSCLC cells • SGLT2 inhibitor canagliflozin causes synthetic lethality in LKB1-mutant NSCLC cells

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Effect of dapagliflozin on colon cancer cell [Rapid Communication]

Cited by 49 publications

References 9 publications

SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials

SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials

Therapeutic Effect of Sodium Glucose Co-Transporter 2 Inhibitor Dapagliflozin on Renal Cell Carcinoma

Synthetic lethality targeting LKB1 mutant and EGFR wild type human non-small cell lung cancer cells by glucose starvation and SGLT2 inhibition

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