Inhibitory effects of canagliflozin on pancreatic cancer are mediated via the downregulation of glucose transporter‑1 and lactate dehydrogenase A

Abstract

Pancreatic cancer is one of the most lethal solid malignancies, with a poor prognosis and a high mortality rate. Pancreatic cancer cells exhibit enhanced glycolysis to maintain their rapid growth. Canagliflozin (CANA) is a sodium-glucose co-transporter 2 inhibitor used for the clinical treatment of diabetes. Recent studies have demonstrated the potential ability of CANA to suppress hepatocellular carcinoma, whereas its therapeutic effects on and mechanisms in pancreatic cancer have rarely been reported. In the present study, the antitumor effects of CANA on pancreatic cancer were investigated. The data obtained indicated that pancreatic cancer growth was effectively suppressed by CANA in a dose-dependent manner, with peak inhibition rates of 54.3 and 57.6% in cultured Capan-1 and PANC-1 cells respectively. The tumor inhibitory rate reached 45.2% in nude mice with PANC-1-derived tumors, suggesting its effective antitumor activity against pancreatic cancer in vitro and/or in vivo. In addition, the combined treatment of Capan-1 and PANC-1 cells with gemcitabine and CANA exhibited a greater efficacy compared with that of treatment with gemcitabine alone. Moreover, glucose uptake and lactate production were decreased, and the mRNA levels of the glycolysis-associated genes, including glucose transporter-1 and lactate dehydrogenase A were decreased, indicating the inhibitory effects caused by the combination treatment on the metabolism of glucose in pancreatic cancer cells. Furthermore, CANA induced apoptosis, notably early apoptosis, and decreased the protein levels of PI3K, p-AKT, p-mTOR and HIF-1α, which indicated that the PI3K/AKT/mTOR signaling pathway was involved in the glycolytic process. These results demonstrated that pancreatic cancer growth was effectively inhibited by CANA via the suppression of glycolysis. This was mediated primarily by the PI3K/AKT/mTOR signaling pathway, revealing the underlying role and potential of this pathway for the clinical treatment of pancreatic cancer. Novel applications for the existing drug CANA can be explored, which could reduce the cost and time required for drug development in the field of drug discovery.

Canagliflozin Modulates Hypoxia-Induced Metastasis, Angiogenesis and Glycolysis by Decreasing HIF-1α Protein Synthesis via AKT/mTOR Pathway

“…Particularly, recent evidence has highlighted the inhibitory effects of several SGLT2 inhibitors on tumors. Xu et al [13] demonstrated that CANA could reduce cell viability and increase apoptotic rate in pancreatic cancer. Dapagliflozin, another SGLT2 inhibitor, could inhibit tumor growth and cancer proliferation by targeting the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway [14].…”

Scoparone inhibits pancreatic cancer through PI3K/Akt signaling pathway

“…In pancreatic cancer, the PI3K/Akt signaling pathway also functions as an antitumor drug target. Xu et al [ 40 ] found that canagliflozin exerted antitumor effects by inhibiting glycolysis through the PI3K/Akt/mTOR signaling pathway, which was improved when combined with gemcitabine, revealing the potential of this pathway in the clinical treatment of pancreatic cancer. However, previous studies investigating the antitumor mechanism of scoparone were insufficient and ambiguous.…”

Drug repositioning in drug discovery of T2DM and repositioning potential of antidiabetic agents

“…A cell study in breast cancer proved that SGLT-2 inhibitors could reduce the viability of breast cancer cells by inducing G1 phase arrest and apoptosis based on the adenosine-monophosphate activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signal pathway [116] . Other evidence indicated that SGLT-2 could also inhibit the proliferation of cancer cells in lung cancer [117] and pancreatic cancer [118] .…”